Male precocious puberty

　　First, Etiology

　　There are many causes of precocious puberty, and GnRH-dependent precocious puberty in females is more common in clinical practice.

　　Second, Pathogenesis

　　1. True precocious puberty

　　(1) Idiopathic precocious puberty: Generally sporadic, with a higher incidence in females (female:male ratio is about 4:1). A few cases may be familial (possibly autosomal recessive inheritance). The cause of this disease is unknown, and it may be due to some factors that cause the hypothalamus to lose control over the development of the gonads (such as the loss of inhibition by the posterior hypothalamus on the anterior hypothalamus), leading to the early secretion of GnRH and pituitary gonadotropins, and triggering the premature activation of the hypothalamus-pituitary-gonadal axis, resulting in precocious puberty. The majority of female patients have sexual development before the age of 8 (the sequence is: breast development - pubic hair appearance - menarche - axillary hair appearance), with pigmentation in the labia and increased vaginal discharge. Boys show increased testicle and penis size, increased scrotal skin creases with deeper pigmentation, increased penile erection, and even spermatogenesis, muscle increase, and subcutaneous fat reduction. Both sexes exhibit a sudden growth spurt and premature bone age, which may lead to premature ossification of the growth plates, making them shorter than normal adults when they reach adulthood. Patients also mature psychologically early, and some may have a sexual history or even a pregnancy history.

　　The patient's serum LH and FSH levels are increased, accompanied by an increase in sex hormone levels. If blood is sampled repeatedly, it can be found that LH is secreted in a pulsatile manner. Idiopathic同性性早熟 is the premature onset of the pubertal process. The artificial demarcation is usually set at less than 2.5 years below the average age of the normal population. Girls before the age of 8 and boys before the age of 9 who show signs of sexual maturation can be diagnosed as precocious puberty.

　　In idiopathic同性性早熟, sporadic cases are more common in females, with a ratio of female to male of about 4:1. In female patients, idiopathic同性性早熟 is 8.5 times more common than organic precocious puberty such as tumors. Conversely, in male patients, organic precocious puberty accounts for 50% to 60% of all cases of precocious puberty. The pathogenesis of idiopathic precocious puberty is unknown, and it is speculated that it may be caused by the premature activity of the hypothalamus.

　　Familial idiopathic precocious puberty mainly affects male members, and some families have been affected for several generations. In extreme cases, signs of sexual maturity may already exist at birth. The mode of inheritance is male-limited autosomal dominant inheritance. The cause of sexual maturation is the activation of testicular function, without the change in gonadotropin secretion during puberty. There are already reports of familial precocious puberty affecting female members, and it is possible that different families have different modes of inheritance.

　　Idiopathic true precocious puberty is characterized by the growth of the testicles in boys, increased skin creases in the scrotum, deepening of pigmentation, growth of the penis and pubic hair, increased erections, and even spermatogenesis. There is an increase in muscle mass and a decrease in subcutaneous fat. In girls, breast development, enlargement of the areola and nipple, development of the labia, pigmentation, increased vaginal discharge, growth of pubic hair, and the onset of menstruation. Ultrasound examination can detect the enlargement of the ovaries. In addition, body straight-line growth accelerates, bone age advances, and eventually the epiphyses are prematurely fused, leading to dwarfism. The patient's psychology, intelligence, and actual age are consistent.

　　An increase in LH and FSH levels, if frequent blood sampling is performed, can be found that LH is secreted in a pulsatile manner. The level of sex hormones also increases accordingly.

　　When clinical manifestations of precocious puberty occur in children, the level of testosterone in male children is almost 100% increased by a single determination of peripheral blood, and the level of E2 in female children is approximately 50% increased. An increase in simple hormone levels is not sufficient to prove central precocious puberty. The proof of central precocious puberty includes two points: ① An increase in gonadotropin levels, with a single determination of peripheral blood, the probability of FSH increase is 80% to 100%, and LH is 20% to 70%. This may be related to the pulsatile secretion of LH, so multiple determinations should be made to make a correct judgment. If a GnRH stimulation test is performed, the secretion response of LH in children with precocious puberty is higher than that in children of the same age who have not developed. ② The growth of the gonads, the size of the testicles can be judged by palpation, while the ovaries require the use of B-ultrasound to achieve the purpose. The next is to exclude organic diseases of the central nervous system. Cerebrospinal fluid examination, cranial CT scan, or magnetic resonance imaging (MRI) can help exclude intracranial diseases. If central precocious puberty is proven, and intracranial lesions and other causes are excluded, it can be diagnosed as idiopathic同性性早熟.

　　Familial male precocious puberty patients have a positive family history, and all patients are male. The activating mutation of the LH receptor gene in males leads to precocious puberty, while the activating mutation of the FSH receptor causes ovarian tumors and excessive secretion of estrogen, leading to female pseudo-precocious puberty.

　　(2) Precocious puberty caused by central nervous system diseases: Often caused by organic brain lesions. Including tumors (such as hypothalamic astrocytoma, glioma, medulloblastoma, hamartoma, pineal gland tumor, teratoma, etc.), infections (such as tuberculous granuloma, encephalitis, brain abscess, etc.), as well as cysts, hydrocephalus, brain trauma, etc. These factors can affect the function of the hypothalamus due to infiltration, scarring, tumor compression, and other reasons, leading to the early activation of the gonadal axis. The exact mechanism is still unclear. However, it has been found that hamartoma itself can secrete GnRH, pineal gland tumors and teratomas can also secrete active substances with gonadotropin activity, and pineal gland tumors can also lead to precocious puberty due to reduced melatonin (melatonin).

　　The development process of this type of precocious puberty is similar to that of idiopathic. The difference between the two types is that idiopathic cases cannot find the corresponding etiology, while this type can find organic intracranial lesions, which can be distinguished by cranial X-rays, CT, MRI, and other examinations.

　　(3) Precocious puberty associated with primary hypothyroidism: Infants due to hypothyroidism have a significantly delayed bone age, and severe cases are accompanied by growth and intellectual disabilities. However, some patients may develop precocious puberty, with early development of external genitalia, skin pigmentation, and girls may have menarche and galactorrhea. The mechanism may be the decrease of thyroid hormones, weakened negative feedback on the hypothalamus, leading to increased secretion of TRH. TRH not only stimulates the pituitary to secrete TSH but also stimulates the secretion of PRL, LH, and FSH. These hormones act on the gonads and breasts, leading to the phenomenon of precocious puberty. This condition can improve after treatment with thyroid hormones.

　　(4) Albright syndrome: Patients with poor bone development, brown pigmented spots on the trunk skin, and often accompanied by precocious puberty. The etiology is unknown, and some believe it is related to the thickening of the skull bone compressing the base of the skull, leading to dysfunction of the hypothalamus. Some cases may have increased secretion of gonadotropin, while others have gonadotropin accompanied by functional ovarian cysts, increased estrogen in the blood, so some people now believe it is a precocious puberty that is not dependent on gonadotropin. This disease is more common in girls, and boys are very rare. Girls show menarche, mature reproductive organs, and breast development, and their sexual development does not follow the normal sequence (the normal sequence is first breast development, then pubic hair growth, and then menarche), so it is believed that it is different from true precocious puberty.

　　（5）Silver syndrome: This disease is associated with dwarfism, congenital hemihypertrophy, and precocious puberty. It was first reported by Silver in 1953. The syndrome has precocious puberty, with increased levels of gonadotropin in the urine, early sexual development, but the bone age is significantly delayed compared to sexual development. The mechanism is unknown. The growth hormone level after birth is within the normal range, but if a large amount of growth hormone treatment is given, the growth rate of height can be rapidly increased, suggesting that it is related to the low sensitivity of the body's cells to growth hormone.

　　（6）Williams syndrome: Williams syndrome is a genetic disease associated with developmental abnormalities of many organs, especially arterial stenosis, mainly due to abnormal elastin. The genetic defect is a 7q11.23 microdeletion on chromosome 7. This is due to the absence of 16 genes, including LIMK1, WBSCR1, WBSCR5, RFC2, and the elastin gene, in this region. Patients have mental retardation and learning disabilities, as well as unique recognition and personality. They often have precocious puberty, with pubic hair development reaching Tanner III stage before the age of 12, normal or advanced bone age, and the cause of the early puberty may be in the hypothalamus or pituitary gland.

　　（7）Testotoxicosis: Also known as familial male-limited gonadotropin-independent sexual precocity with premature Leydig cell and germ cell maturation. This syndrome was first reported in 1981. The affected children have an enlarged penis, sometimes with an enlarged penis at birth. The Leydig cells and Sertoli cells in the testes mature prematurely and spermatogenesis occurs, sometimes accompanied by Leydig cell hyperplasia. The longitudinal growth and bone age of the children are advanced, with well-developed muscles. The levels of LH and FSH in the blood at baseline and after GnRH stimulation are similar to those before puberty, generally without the pulsatile secretion characteristics of LH. The blood testosterone level increases to adult levels, and the level of DHEAS is comparable to the bone age, but higher than that of normal individuals of the same age. The characteristic of this syndrome is that the maturation and hyperplasia of Leydig cells and germ cells cannot be inhibited by GnRH agonists, and the secretion of testosterone is also not suppressed. Those with penile erection and ejaculation may have fertility, and the secretion of LH and the response to GnRH at this time are the same as normal adults, indicating the existence of secondary GnRH-dependent precocious puberty factors. Some adult patients have impaired spermatogenesis and elevated blood FSH levels. Occasionally, this syndrome is sporadic, but the vast majority is familial, and there have been reports of a family with nine consecutive generations of disease. Women carry the activated mutation of the LH receptor gene, while men are affected.

　　The etiology of this condition has been basically clarified. The LH/HOG receptor is a glycoprotein with a molecular weight of 80,000 to 90,000. The receptor gene is located at 2p21. The LH/HOG receptor is a member of the G protein-coupled receptor family. There are currently at least 10 different types of activating mutations, mainly occurring in the 542 to 581 region. Due to activating mutations, Leydig cells and germ cells are excessively and chronically stimulated, leading to precocious puberty.

　　2. Male pseudo-precocious puberty

     The precocious puberty in this group of cases is not related to the hypothalamic-pituitary gonadotropic center, and is not the result of activation of the central nervous system GnRH pulse generator. This type of precocious puberty is incomplete.

　　(1) Tumors that produce gonadotropins: These can be seen in choriocarcinoma or teratoma producing HCG, or liver tumors producing LH-like substances, which promote increased secretion of sex hormones. Since only one type of gonadotropin is produced, true precocious puberty cannot be caused. Almost all patients with this condition are male. The external genitalia develop and increase in size, but there is no fertility.

　　(2) Premature and excessive androgen production: This can be caused by Leydig cell tumors of the testes (leading to unilateral testicular enlargement and significantly elevated plasma testosterone) or adrenal lesions (such as congenital adrenal hyperplasia caused by 21-hydroxylase or 11-hydroxylase deficiency, impeding cortisol synthesis, increasing ACTH secretion, and stimulating increased androgen secretion by the adrenal glands). There are also a few cases caused by iatrogenic or excessive use of androgens.

　　(3) Excessive estrogen production: Conditions such as granulosa cell tumors of the ovary, ovarian cysts, or tumors that secrete estrogen can cause premature development of female external genitalia and secondary sexual characteristics, but without maturation of germ cells.

　　Above are adrenal or gonadal diseases that cause an excessive production of sex hormones, all showing elevated urinary 17-KS, and the dexamethasone suppression test can suppress, usually indicating adrenal hyperplasia, while those that do not suppress indicate adrenal tumors or gonadal tumors.

　　(4) Overuse of exogenous androgens or estrogens: Tiwary et al. reported that food containing exogenous estrogens can lead to false precocious puberty in females, which can return to normal after stopping medication.

　　The acceleration of bone maturation can eventually lead to a final height lower than the target height. In cases with intracranial tumors and other central nervous system lesions, there may be headaches, vomiting, changes in vision, or other neurological symptoms and signs. McCune-Albright syndrome may have pseudocysts, deformities, and fractures in bones, and may be accompanied by hyperfunction of the thyroid, adrenal glands, pituitary, and parathyroid glands, manifested as nodular goiter, hyperthyroidism, nodular hyperplasia of the adrenal glands, excessive secretion of growth hormone leading to gigantism or acromegaly, etc.

　　1. True precocious puberty

　　1, Idiopathic precocious puberty:It is generally sporadic, more common in females (female∶male is about 4∶1), and a few may be familial (possibly belonging to autosomal recessive inheritance), the etiology is unknown. Females often show development before the age of 8, with the sequence of breast development → the appearance of pubic hair → the onset of menstruation → the appearance of armpit hair, the development of the labia (with pigmentation), and an increase in vaginal discharge.

　　Males experience sexual development before the age of 9, with the testicles and penis growing larger, the scrotal skin wrinkles increasing with pigment deepening, increased penile erection, and even sperm production. There is an increase in muscle mass and a decrease in subcutaneous fat.

　　Both sexes show a sudden increase in height, premature bone age, which can eventually lead to early fusion of epiphyses, resulting in a shorter adult height. Sexual psychology matures early, and a few may have a sexual history or pregnancy history.

　　2, Precocious puberty caused by central nervous system diseases:The clinical manifestations are similar to those of idiopathic cases, but this type may also have manifestations related to organic lesions of the nervous system. The main method of differentiation relies on cranial X-ray, CT, MRI, and other examinations.

　　3, Primary hypothyroidism (hypothyroidism) with precocious puberty:A few children who had hypothyroidism before the preschool age may have precocious puberty, which may be due to decreased thyroid hormone levels, weakened negative feedback, causing an increase in hypothalamic TRH secretion. TRH not only stimulates the pituitary to secrete more TSH, but also stimulates the secretion of PRL, LH, and FSH, leading to precocious puberty.

　　4, Multiple osteofibrous dysplasia (Albright syndrome) with precocious puberty:Patients have poor bone development, brown pigmented spots on the trunk skin, often accompanied by precocious puberty, the etiology is unknown, more common in girls, boys are extremely rare, and the sequence of sexual development is different from normal: normal development usually precedes breast development → pubic hair growth → the onset of menstruation, while in this disease, menstruation occurs first (the reproductive organs are fully developed), followed by breast development.

　　5, Silver syndrome with precocious puberty:This syndrome is characterized by dwarfism, congenital hemihypertrophy with precocious puberty, normal growth hormone levels at birth, but if a large amount of growth hormone treatment is given later, there is a rapid increase in height, which is speculated to be related to the low sensitivity of target cells to growth hormone. The characteristic of precocious puberty in this syndrome is that the bone age is significantly delayed compared to sexual development.

　　6. Williams syndrome with precocious puberty:This syndrome is accompanied by many organ developmental malformations, especially genetic diseases with hereditary defects of arterial stenosis, the genetic defect is located at the 7q11.23 locus, with 16 genes missing, including LIMK1, WBSCR1, WBSCR5, RFC2, and elastin genes, etc. The clinical manifestations are intellectual retardation, learning disorders, special cognitive and personality characteristics, often accompanied by precocious puberty, and differential diagnosis is based on the detection of gene deletion.

　　7. Testicular toxicity with male precocious puberty:This disease is also known as familial male non-gonadotropin-dependent precocious puberty with premature development of Leydig cells and germ cells, and the patients show an enlarged penis, some have an enlarged penis at birth, the Leydig and Sertoli cells of the testicles mature prematurely and spermatogenesis occurs, sometimes accompanied by Leydig cell hyperplasia. The longitudinal growth and bone age of the children are advanced, the muscles are strong, and those with erections and ejaculation may have fertility. A few adult patients have spermatogenic disorders, the vast majority are familial, a few are sporadic, and the cause is a missense mutation in the LH/HCG receptor gene (2p21).

　　8. Precocious puberty caused by treatment of congenital adrenal hyperplasia:For patients with congenital adrenal hyperplasia such as 11-β-hydroxylase and 21-hydroxylase deficiency, after treatment with glucocorticoids or simultaneously with mineralocorticoids, the plasma ACTH level is suppressed, the production of sex steroid hormones by the adrenal glands is reduced, but due to the delay in diagnosis and treatment during this period, the patient's bone age is advanced. If the patient has reached the threshold value of puberty onset, the patient may experience the activation of the hypothalamus-pituitary-gonadal axis, causing precocious puberty. Similarly, patients who have previously been treated with sex steroid hormones may also experience this.

　　II. Pseudo-precocious puberty

　　The main difference between the clinical manifestations of pseudo-precocious puberty and true precocious puberty lies in sexual development, which is incomplete, that is, it only shows the development of certain secondary sexual characteristics, but there is no maturation of germ cells (sperm and ovum), and no fertility.

　　Idiopathic precocious puberty is generally sporadic, with a few cases showing familial characteristics (which may be due to autosomal recessive inheritance). Genetic and genetic testing can be done to detect it early. Try to minimize the influence of sex hormones in the environment: such as pollen, honey, royal jelly, chicken embryo, silkworm pupae; animal foods that grow quickly, out-of-season fruits, soybeans and their products, adult health supplements such as snow frog, Cordyceps sinensis, ginseng, certain oral liquids that claim to make children 'taller and stronger', 'high hormone' foods such as chicken necks, fried foods, etc. Adult cleaning and cosmetic products, etc. Avoid contact with scenes and text related to sexual content in films, books, and newspapers. Avoid excessive light exposure: such as turning off the lights for sleep at night. Exercise more, eat a balanced diet, avoid high-calorie foods, and prevent overweight and obesity.

　　First, laboratory examination

　　1. Determination of sex hormones and gonadotropins

　　The secretion of sex hormones and gonadotropins has obvious age characteristics. Before 2 years of age, the levels of FSH, estradiol in female children, and testosterone in male children are all high. After 2 years of age, these levels decrease significantly, and then increase again after the onset of puberty. Before the onset of puberty, the level of testosterone in male children is less than 1.75nmol/L, and estradiol is less than 37.5pmol/L; in female children, testosterone is less than 0.7nmol/L, and estradiol is less than 75.0pmol/L. In true precocious puberty, LH and FSH levels increase and show periodic changes. Before the establishment of a periodic feedback relationship, there are diurnal fluctuations, with an increase at night during sleep. In children with idiopathic precocious puberty, the serum levels of FSH, LH, testosterone, and estradiol are all higher than those of normal children of the same age. However, due to the overlap between the normal upper limit and the pathological lower limit, there is no strict boundary, so its diagnostic reference value is less (especially in the early stage). If necessary, DHEAS, progesterone, 17-hydroxyprogesterone, HCG, and the relationship between DHEAS and actual age and bone age can reflect the initial appearance of adrenal function, which is helpful for the diagnosis of true precocious puberty. When gonadotropins do not increase, but estrogen increases, consider ovarian or adrenal tumors. If androgens are significantly elevated, consider the secretion of ectopic HCG. Elevated blood progesterone levels suggest a corpus luteum tumor. Common reproductive hormone changes in precocious puberty.

　　2. GnRH or clomiphene stimulation test

　　It can understand the functional status of the hypothalamus and pituitary.

　　(1) GnRH stimulation test: In true precocious puberty, the level of LH is observed 30 minutes after the injection of GnRH, and FSH is increased by 2 times or more than the baseline value. In false precocious puberty and true precocious puberty with an underdeveloped hypothalamic-pituitary-gonadal axis, there is no response or a low response. In individuals with premature development of breast tissue, the response to the test is a significant increase in the FSH peak, while the LH response is not prominent. It was previously believed that the response to the stimulation of LH alone could differentiate between premature breast development and central precocious puberty. Recent studies have found that in infants and young children under 4 years of age with premature breast development, the peak LH response to the test can be greater than 20U/L. Therefore, it is considered that infants and young children under 4 years of age cannot be diagnosed solely based on the LH response, but should be judged by combining the responsiveness of FSH to GnRH stimulation. It is generally believed that in central precocious puberty, the ratio of LH/FSH after GnRH stimulation is greater than 1, while in simple premature breast development, the ratio of LH/FSH is less than 1.

　　(2) Clomiphene stimulation test has certain value in judging the maturity of the hypothalamus-pituitary-gonadal axis, but it is currently less used. Before the test, measure FSH and LH as the baseline. Then take 100mg of clomiphene, for 5 consecutive days. On the 6th day, re-measure FSH and LH after taking the test. If it increases by 50% compared to the baseline value, it indicates that the hypothalamus-pituitary-gonadal axis is mature, which is helpful in distinguishing true and false precocious puberty.

　　3. Urine 17-ketone determination

　　For patients with congenital adrenal cortical hyperplasia or adrenal cancer, the urine 17-ketones increase, and desmopressin suppression test can be performed. In patients with adrenal cancer, the increase in urine 17-ketones cannot be suppressed by low-dose desmopressin. Congenital adrenal cortical hyperplasia has elevated plasma 17-hydroxyprogesterone, elevated plasma 11-deoxycorticosterone, and increased urine pregnenolone according to different types.

　　Secondly, imaging examination

　　1. X-ray film of the left wrist for determining bone age:Bone age exceeding 2 years above the actual age should be considered as precocious puberty, and delayed bone age suggests hypothyroidism.

　　2. X-ray film of sella turcica:Fundus examination, visual field examination, etc., are helpful to understand whether there are intracranial lesions. Suprasellar calcification suggests craniopharyngioma, pineal calcification with enlargement and deformation of the sella turcica suggests intracranial tumors. Intracranial tumors can cause papilledema of the fundus and changes in visual fields.

　　3. Electroencephalogram:In cases of brain topographic map and organ-specific lesions, there are often abnormal changes. Some children with idiopathic precocious puberty may show diffuse abnormalities on electroencephalography, including abnormal slow waves with periodic activity and sharp waves, spike waves, etc.

　　4. Abdominal and pelvic ultrasound examination:Can understand the size and shape of the adrenal glands and ovaries, as well as the ovarian condition.

　　5. CT and MRI examination: CT and MRI head examination:Understanding intracranial lesions, especially helpful for identifying intracranial tumors, is also of great importance for excluding secondary true precocious puberty. The above examinations are all normal in patients with idiopathic true precocious puberty, and they are also of great value in distinguishing adrenal tumors and ovarian tumors. Some people use MRI to diagnose central precocious puberty, and classify according to the concavity degree of the superior pituitary (Grade 1: obvious concavity, Grade 2: mild concavity, Grade 3: flat, Grade 4: mild protrusion, Grade 5: obvious protrusion), believing that pituitary grading is of great value in diagnosing precocious puberty in prepubertal children, and those above Grade 4 can be highly suspected of central precocious puberty.

　　Food that can cause precocious puberty in children:

　　1. Tonifying food that can be taken as medicine:Including Cordyceps sinensis, ginseng, dried longan, dried lychee, Astragalus membranaceus, and Radix adenosae, etc. Especially Guangdong people, like to cook soup with medicinal food. Traditional Chinese medicine points out that the more tonifying food, the more it will change the normal endocrine environment of children, causing an imbalance in physical and mental development.

　　2. Poultry meat, especially poultry necks:Most of the poultry sold on the market today are fed with feed mixed with rapid growth promoters, and the residues of the maturation agents are mainly concentrated in the glands of the heads and necks of the poultry. Therefore, eating duck necks and goose necks has become a high-risk behavior for promoting early maturation.

　　3. Out-of-season vegetables and fruits:Strawberries, grapes, watermelons, tomatoes, etc., pears, apples, oranges, and peaches that are sold on the market at the end of spring and early summer are almost matured out of season or prematurely with the help of growth promoters, so it is necessary to avoid giving them to children under the age of 10.

　　4. Fried foods:Especially the excessive calories from fried chicken, French fries, and potato chips can be converted into excessive fat in children's bodies, causing endocrine disorders and leading to precocious puberty; and after repeated heating, the oil becomes oxidized and denatured, which is also one of the causes of precocious puberty. Children who visit fast food restaurants twice a week or more and often eat fried and puffed foods have a 2.5 times higher chance of precocious puberty than ordinary children.

　　First, treatment

　　1. Treatment of True Precocious Puberty

　　(1) Medroxyprogesterone acetate (MPA) or Chlormadinone: They can directly inhibit the GnRH pulse generator in the hypothalamus and the release of gonadotropins from the pituitary. In addition, they may also have inhibitory effects on the gonadal steroid receptor of the target tissue. The dose is 4-8mg/d, which has inhibitory effects on the development of the sexual organs. The disadvantages include no effect on the acceleration of bone age development, atrophy of the target organs of gonadal steroids after long-term use, and slow recovery of menstruation after discontinuation of the drug. Due to its corticosteroid-like effects, it can cause weight gain, hypertension, and Cushing-like syndrome. Animal experiments have found that it can induce breast cancer. Ishii et al. reported that a long-term oral dose of 110-170mg/m2 of cyproterone acetate (Cyproterone acetate) daily, combined with or alone with buserelin acetate 700-900μg/m2, administered nasally by spray, achieved a height of 170cm in GnRH-dependent precocious puberty boys at the age of 15.3 years, indicating that GnRH analogs can also be used to treat GnRH-dependent precocious puberty.

　　(2) Cyproterone Acetate (Cyproterone, Cyproterone acetate): This is a derivative of progesterone, which can bind to androgen receptors, blocking the effects of testosterone and DHT at the receptor level, and competitively blocking the GnRH receptor in the pituitary, inhibiting the synthesis and release of gonadotropins. This drug was first used to treat prostate cancer and was used to treat precocious puberty in 1962. The oral dose is 70-100 mg/m2 daily, or 100-200 mg/m2 by intramuscular injection every 2-4 weeks. It has a significant inhibitory effect on the maturation of sexual organs, but the inhibitory effect on bone age acceleration is uncertain. Side effects may include headache, fatigue, insomnia, and nausea, and it also has an inhibitory effect on ACTH secretion, so long-term use requires monitoring changes in adrenal cortical function.

　　(3) Gonadotropin Releasing Hormone Agonists (GnRH-A): GnRH is a single-chain 10-amino acid structure, a derivative with altered amino acid structure that is several to several tens of times more potent than the prototype molecule. The physiological effects of GnRH have a dose-dependent dual nature; in small dose pulse injection, it excites the pituitary gonadotropin, while in continuous high-dose injection, it inhibits it. This principle is used in clinical treatment of precocious puberty. Currently, buserelin is widely used in clinical practice, with a dose of 10-20 μg/kg daily, administered subcutaneously or by nasal inhalation of 600 μg every 6 hours. Deslorelin (Luteinizing Hormone-Releasing Hormone, LRH), with a dose of 4-10 μg/kg daily, administered subcutaneously. Or 4 μg/kg daily LRH nasal inhalation. Generally, after injection of GnRH agonists, GnRH, testosterone, and E2 levels may temporarily rise within a few days. After one week, they gradually decrease to prepubertal levels, and ultimately testosterone and estrogen are completely suppressed. After 6 months of treatment, growth rate can decrease to 5-6 cm/year. Secondary sexual characteristics may change; girls may experience breast shrinkage, hair reduction, and decreased menstrual flow, while boys may have reduced testicle size, hair thinning, and decreased penile erection. Long-term use has not shown significant side effects, but use should be discontinued when reaching puberty age.

　　Now there are applications of GnRH antagonist analogs for treatment, which can quickly reduce the level of sex hormones (avoiding the stimulation phase after the use of GnRH-A), with better efficacy.

　　For patients with Albright's syndrome, it is currently believed that it is not true precocious puberty caused by the early activation of the gonadal central axis, and such drugs are ineffective. In addition, familial male precocious puberty is ineffective with GIRH-A, and it can be treated with a combination of spironolactone (Antisterone) and testosterone enanthate (a aromatase inhibitor).

　　(4) Ketoconazole: It can be used for male idiopathic precocious puberty patients who are ineffective with GnRH-A treatment. The drug mainly affects the 17-20 cleavage enzyme of steroids, thereby interfering with testosterone production. Taken orally twice or three times a day at a dose of 200-600mg.

　　(5) Danazol: It is a synthetic steroidal heterocyclic compound, a derivative of 17α-ethynyl testosterone, with the effects of inhibiting ovarian estrogen synthesis and ovarian follicle development, as well as anti-gonadotropin hormone and mild androgenic effects. It can also be used for the treatment of precocious puberty.

　　II. Treatment of False Sexual Precocity

     Since it is a non-GnRH-dependent precocious puberty, treatment with GnRH agonists (GnRH-A) is ineffective, and methylergonovine, testosterone enanthate, spironolactone (Antisterone), ketoconazole, etc. can be selected according to the condition. In normal adolescent development, male body development and bone maturation depend on the action of estrogen. Feuillan et al. advocate the use of testolactone (Testolactone) combined with anti-androgenic drug spironolactone for treatment. If it is GnRH-dependent precocious puberty, GnRH analogs can be used for treatment. Spironolactone, testosterone and Deskorelin can be used to treat patients with familial male precocious puberty, so that excessive growth and bone age can be controlled within the normal range.

　　In the treatment of the primary disease, patients with congenital adrenal hyperplasia can use corticosteroids supplemented with necessary corrective treatment (such as resection of the hypertrophied clitoris, etc.). Surgery or radiotherapy should be performed for intracranial, testicular, ovarian, adrenal and other tumors.

　　II. Prognosis

　　False sexual precocity only has the development of secondary sexual characteristics, no fertility.