female precocious puberty
Introduction
Introduction "female precocious puberty", that is, puberty development is significantly advanced, because the initial time of puberty development varies greatly in each normal child, it is difficult to determine the absolute limit of normal and precocious puberty at the beginning of puberty, generally considered to be 8 years old before the girl Any one or more secondary sexual characteristics such as enlarged mammary gland, pubic hair growth, mane growth, or menarche begin before the age of 10, which is female precocious puberty. Some scholars also advocate that children's puberty and sexual development are earlier than local normal children. Precocious puberty is the average developmental age of 2 or more than 2.5 standard deviations. Female precocious puberty accounts for about 0.2% of all women.
Cause
Cause
(1) Causes of the disease
classification:
True precocious puberty
Caused by increased gonadotropin. Gonadotropin increase causes follicular development, and even ovulation has fertility, which is homosexual precocity or complete precocious puberty. The most typical case is Lina Medinam in Peru, who has a full-term pregnancy at 5 years and 10 months, and has a cesarean section.
2. pseudo precocious puberty
Caused by increased gonadal steroids, such as increased estrogen, homosexual precocity, and increased androgen, heterosexual precocious puberty, incomplete precocious puberty, no fertility.
(two) pathogenesis
True precocious puberty
Complete homosexual precocity. Due to the early development of the gonad axis and the early onset of puberty, the sexual maturation process proceeds in the normal puberty sequence, and the hypothalamic-pituitary-gonadal axis function is established, with an ovulatory menstrual cycle and fertility.
(1) idiopathic precocious puberty (idiopathic precocious puberty) also known as constitutional or functional precocious puberty, is a common cause of true precocious puberty in children, accounting for 80% to 90% of girls precocious puberty.
The cause was unknown. After careful examination, no pathological changes were found, but about half of the children had abnormal EEG, and the basic levels of gonadotropins and sex hormones increased. The LH pulse frequency and amplitude are all in the normal puberty range for GnRH stimulation. The pathogenesis of this disease has not yet been fully understood. It may be due to some unclear reasons that the central nervous system physiological mobilization point or hypothalamic inhibition of gonadal development is out of control, and the hypothalamic GnRH or pituitary gonadotropin premature secretion is increased. The disease has a family morbidity tendency, which is more obvious for men, and the girls are mostly sporadic and rare. It is autosomal recessive, and children with positive family history have a late onset and relatively mild condition (after boys are 7 years old, girls are more than 6 years old), and the incidence of boys is higher than that of girls.
Generally, the mammary gland develops first, followed by pubic hair. In most cases, the pubic hair appears along with the development of the external genitalia. With the development of the external genitalia, the mane and menstruation appear, the menstrual cycle begins to irregular, and does not ovulate. When the ovary is fully mature, the menstrual cycle gradually changes and ovulation occurs. At this time, the girl may be pregnant. There have been reports of a 5.5-year-old girl getting pregnant in the literature. Height, weight gain and bone maturity are accelerated during sexual development. This rapid growth is mainly due to the stimulation of GH and IGF-1 by gonadal steroids. However, not all patients develop faster, but also have slow development or fast and slow. Due to the early closure of the epiphysis, there is a high childhood, adult stunt development curve, about 1/3 of the child's adult height is less than 152cm, the development of teeth and intelligence is generally consistent with their age. Except for the height of the patient, the rest of the patient is normal. The mental state is proportional to the actual age. The growth hormone binding protein (GHBP) is significantly increased in the precocious puberty, but with height, age, youth stage, IGF-1 and testosterone. /Estradiol levels are not related, and may be related to increased body fat content.
Precocious puberty girls do not have premature amenorrhea, but the risk of developing breast cancer in adulthood is often higher than that of normal people. The frequency and amplitude of gonadotropin, LH and LH pulse are like puberty. Girls who are sick from 6 years old are often accompanied. Adrenal function is early in advance.
(2) true precocious puberty caused by central nervous system diseases: central nervous tumors or non-neoplastic diseases such as hydrocephalus, infection, cysts, trauma, etc. can cause true precocious puberty. It accounts for about 10% of female precocious puberty. More than half of them are caused by tumors. Common tumors include pineal tumor, optic glioma, hypothalamic hamartoma, suprasellar teratoma, neurofibromatosis, astrocytoma, ependymoma, and the like.
How the intracranial lesions stimulate puberty has not been known so far. It may be the local infiltration of the intracranial tumor, the scar structure and the increase of intracranial pressure, which affect the nerve pathway of the GnRH pulse generator in the brain. The GnRH pulse appears early, and the puberty develops and the symptoms of precocious puberty appear. For example, hamartoma is a non-progressive tumor composed of ectopic hormone secreting neurons, fiber bundles, and glial cells. The ectopic GnRH secreting cells pulsate GnRH. It has been reported that the GnRH-containing fibers in this tumor are connected to the hypothalamic median ridge, but the GnRH release caused by hamartoma is not controlled by the intrinsic central nervous system, and is an atopic CnRH pulse generator. The age of onset of sexually precocious puberty is often small, mostly less than 3 years old, and can be combined with central nervous system abnormalities, such as epilepsy, dementia and other changes. Due to the widespread use of CT and MRI in recent years, the diagnosis rate of this disease has increased year by year, and about 10% of the patients have sexual precocious performance. In addition, arachnoid cysts can also cause hypothalamic and pituitary dysfunction, and physiological precocious puberty.
The development of sexual characteristics in patients with precocious puberty caused by central nervous system disease is similar to that of idiopathic, except for the development of sexual characteristics, accompanied by other corresponding symptoms of intracranial disease, such as polydipsia, polyuria, fever, obesity or excessive Weight loss, mental disorders, mental retardation, headache, vomiting, convulsions, limb paralysis and visual impairment. It is worth noting that a considerable number of patients, intracranial tumors grow slowly, often first appear sexual precocious performance, and then gradually appear symptoms and signs of intracranial hypertension or nerve tissue damage. The mechanism by which hydrocephalus causes precocious puberty and amenorrhea is unclear. About 22 cases of hydrocephalus combined with amenorrhea and several cases of precocious puberty have been reported. After hydrocephalus drainage treatment, most cases can cause the initiation and maintenance of the normal reproductive cycle. It is believed that the mechanism leading to abnormal function of reproductive system may be related to GnRH, but the exact pathway of hydrocephalus affecting the hypothalamic GnRH system is still unclear, which may be related to the destruction of mechanical compression, ischemia and nerve conduction feedback pathway.
(3) True precocious puberty caused by other causes: congenital adrenal hyperplasia such as 11-hydroxylase and 21-hydroxylase deficiency patients treated with glucocorticoids or simultaneous mineralocorticoids, plasma ACTH levels are inhibited, adrenal gland The production of gonadal steroids is reduced, but due to the delay in diagnosis and treatment, the patient's bone age is advanced. If the bone age limit value of puberty is reached, the patient may have activation of hypothalamic-pituitary-gonadal axis function, causing precocious puberty, which has been used in the past. This is also the case with patients treated with gonadal steroids.
2. Female pseudo precocious puberty
Pseudo-precocious puberty is incomplete homosexual precocious puberty. Estrogen or exogenous estrogen derived from gonads or adrenal glands stimulates target organs excessively, causing secondary sexual development and menstrual cramps. Because there is no normal hypothalamic-pituitary-gonadal axis function, there is no fertility.
(1) neoplastic pseudoprecocious puberty: follicular cysts and ovarian tumors (granulosa cell tumor, vesicular cell tumor, etc.) are the most common causes of female pseudoprecocious puberty. "Autonomic" follicular cysts, which secrete estrogen, promote sexual development and vaginal bleeding, and the concentration of estrogen secreted by them fluctuates greatly. Most ovarian tumors are bilateral, gonadotropin levels are inhibited, and LH is slow to respond to GnRH stimulation. B-ultrasound can help identify follicular cysts and substantial ovarian tumors, but many patients eventually need a laparotomy to confirm the diagnosis. Follicular cysts generally do not require surgery. It has recently been reported that an ovarian tumor derived from the residual tissue of the adrenal gland causes pseudo precocious puberty, and its tissue source is determined by measuring the P450C11P and P450 C21 specific genes expressed by the adrenal cortex. Ovarian teratomas, chorionic epithelial carcinoma, germ cell tumors, liver tumors, if only chorionic gonadotropin (HCG) secretion does not cause female precocious puberty (unless estrogen is also secreted), because in the absence of FSH, pure HCG LH does not stimulate the ovary to synthesize estrogen. The adrenal gland is a tumor that can cause pseudo precocious puberty, and its estrogen is derived from the tumor or the secreted androstenedione is transformed from the gland. The main lesions of Peutz-Jeghers syndrome are mucosal skin pigmentation, digestive tract polyps and sex tumors. Incomplete precocious puberty due to the secretion of estrogen by the tumor, occasionally accompanied by supporting cell-stromal cell tumor.
Recently, Speiser et al reported a case of a 10-year-old girl with portal hypertension due to neonatal portal vein shunting and hepatocyte steroid hormone metabolism, resulting in increased blood sex hormone levels, and precocious ovarian and ovarian prolapse . The patient developed pubic hair at 6 years of age, 7 years old with mammary gland development, and 10 years old with obvious acne and clitoris hypertrophy. Determination of blood basal hormone levels: androstenedione 413ng / dl, testosterone 226ng / dl, E2160pg / ml, liver transaminase normal, mild abnormal blood coagulation index, ACTH stimulation test showed glucocorticoid hormone production defects, dexamethasone inhibition The test showed a slight decrease in androstenedione and testosterone. The LHRH excitatory test showed that LH and FSH showed adolescent-like reaction. B-ultrasound showed ovarian enlargement and multiple follicles. The exploration revealed bilateral ovarian enlargement. Pathological examination was vesicular cell hyperplasia. Immunohistochemistry showed that stromal cells had expression of steroid synthase. There was no change in blood androstenedione and testosterone at 1 month after operation, while E2 decreased to 56 pg/ml. Leucylide acetate (leuprolide) Acetate) significantly reduced testosterone levels, followed by oral contraceptives, reduced to 50 ng / ml, menstrual cycle recovery. This case reminds us to pay attention to the history of portal hypertension and blood sex hormone levels in children with precocious puberty.
(2) McCune-Albright syndrome: This disease is characterized by irregular skin brown pigmentation spots, slow progression of multiple bone dysplasia and precocious puberty (multiple bone dysplasia). see. This is due to the G-alpha complex Gs alpha subunit mutation resulting in sustained activation in the absence of LH. It is therefore attributed to the precocious puberty type that does not depend on GnRH. Due to the autonomic activation of the ovary, autonomous cystic follicles appear, the secretion of estrogen increases, no ovulation, there are multiple vesicular follicles in the ovary, sometimes a single larger follicular cyst, and the ovarian asymmetric cyst can be spontaneously locked, but not Inhibition by GnRH agonists. The basal level of LH is at prepubertal level, and LH is not sensitive to GnRH response, but responds to aromatase inhibitors. The disease can also involve other endocrine diseases, such as the thyroid (nodular hyperplasia with toxic goiter), adrenal gland (multiple proliferative nodules with adrenal hyperfunction). Pituitary (pituitary tumors with GH or PRL secretion) and parathyroid (adenomas or hyperplasia) and other diseases, resulting in excessive secretion of thyroxine, adrenocortical hormone and GH, PRL and other hormones. Therefore, it is considered to be a multiple endocrine adenoma syndrome.
(3) Hypothyroidism: hypothyroidism in young children and adolescents, most children with delayed growth, sexual development retardation, amenorrhea, a small number of precocious puberty, manifested as mammary gland development, enlarged labia minora, vaginal mucus smear visible Changes in the effects of estrogen. Generally, there is no pubic hair growth, some children will have irregular vaginal bleeding, but often no puberty growth acceleration, but short stature, bone age often lags behind the actual age. Single or multiple small cysts may appear in the ovary.
The exact mechanism that causes this disease is unclear. FSH is slightly higher than normal, and FSH pulse secretion increases at night. It is concluded that there may be two reasons: 1 The hypothalamic GnRH pulse generator is slightly activated, which stimulates the secretion of pituitary FSH without exciting LH secretion. Gnumbach et al believe that pituitary gonadotropins are cross-reactive with the feedback mechanism of thyroid hormones, so cells that secrete gonadotropins respond to thyroid hormone deficiency like TSH-secreting cells. 2 increased hypothalamic TRH release, causing increased FSH secretion, often accompanied by elevated PRL, so galactorrhea may occur. As GH declines, bone maturity is delayed without height and length.
(4) Asymmetric short stature dysplasia syndrome (Russell-Silver syndrome): This disease is rare, due to brain dysfunction, resulting in short stature and delayed bone age. Head and facial bone development abnormalities and precocious puberty, showing an inverted triangle face, the mouth angle is downward, the body is obviously asymmetrical, the finger, the phalanges are pointed or the fifth finger (toe) is bent, short deformity.
(5) Exogenous estrogen-induced pseudo-precocious puberty: including estrogen-containing drugs such as oral contraceptives and other estrogen-containing foods can cause, young girls eat oral contraceptives, breast development and vaginal bleeding , nipple, areola brown pigmentation, there are reports of this disease caused by the young girl sucking oral contraceptive mother's milk.
3. Sexual developmental variation
(1) Precocious thelarche: refers to the development of one or both breasts before the age of 8 years, no other sexual development, no bone age. It is common in young girls of about 2 years old, rarely more than 4 years old, can naturally subside after several months or years, a few can continue to adolescence, sometimes the development of breast development is slow, there is a feeling of induration, nipple development is not obvious, estrogen pair The effect of vaginal cells is not obvious, and the uterus does not increase. The level of estrogen is slightly higher or normal, the ovary generally does not increase, and single or several small follicles may appear. The follicle may sometimes retreat, sometimes appear, and often coincides with changes in the mammary gland. FSH reached the level of puberty and responded to GnRH. LH was at the level before puberty and had no obvious response to GnRH.
The pathogenesis of the disease is unknown, may be: 1 temporary FSH and / or LH secretion, promote follicular development, temporary increase in estrogen; 2 prepubertal breast tissue is sensitive to low levels of estrogen in the circulation; 3 neonatal gonadotropin The secretion of hormones was not stopped in time, the gonadotropin in the body caused the secretion of estrogen, and maintained a certain level in the circulation; 4 the premature development of the mammary gland, the increase of serum sex hormone binding globulin (SHBG), the decrease of testosterone and free testosterone combined with non-SHBG Reduced bioavailability may result in a change in the ratio of estrogen to androgen in the breast.
In addition, a clinical type between simple premature breast development and central precocious puberty has been found. Stanhope reported that 10 children had spontaneous gonadotropin secretion and ovarian enlargement in addition to premature mammary gland development, and the morphological changes of the ovary were somewhere in between. The treatment with GnRH-A was ineffective, suggesting that the mammary gland Developmental independent of gonadotropins, cyclical changes are most likely due to abnormal follicular proliferation, a condition known as the variant of the longitudinal hyperthermia (thelarche variant). It has been reported that girls who have had premature breast development in childhood often have hyperinsulinemia, decreased IGFBP-1 and SHBG, and increased free androgen index. Therefore, it is considered that children with premature breast development should be followed up for a long time.
(2) Early adrenal function (pubic hair early appearance): refers to a sexual developmental variation in the development of pubic hair and pubic hair without other sexual characteristics. Frequently occurring in children after 6 years of age, as early as only a few months, due to premature secretion of adrenal androgen or hair follicles are too sensitive to androgen stimulation, but it is also reported that ovarian cysts temporarily secrete androgen-induced Case. DHEA, DHEAS, androstenedione and testosterone, urinary 17-ketosteroids increased, the degree of elevation is comparable to the normal hormone development stage II hormone levels, gonadotropin is not high, GnRH response like prepuberty, bone age Both body length and body length are slightly higher than the actual age, but there is no bone over-maturation and no growth spurt. If the bone age is too high and testosterone reaches adolescence level, the steroid hormone synthase deficiency may be considered. The disease is generally self-limiting, without treatment, and can enter puberty normally.
(3) Single sexual precocity: It is a rare sign of incomplete sexual precocity. The clinical manifestation is that the girl has a single menstrual inflow, but no other sexual development. The young girls who are common in 1 to 6 years old are often transient and have a good prognosis. Estrogen levels fluctuate as high as pre-pubertal estrogen levels, and gonadotropins do not. May be associated with increased transient ovarian function, and some are seen in children with ovarian cysts.
4. Excessive secretion of androgenetic premature androgen causes masculinization in women. Congenital adrenal hyperplasia or adrenalinal syndrome due to lack of 21 hydroxylase or 11-hydroxylase, glucocorticoid synthesis is blocked, inhibition of pituitary ACTH is reduced, ACTH synthesis is increased, and adrenal hyperplasia is stimulated Including reticular cell proliferation, increased synthesis of androgens. In addition, 17-hydroxyprogesterone and progesterone cannot be converted to glucocorticoids, and the conversion to androgen is increased. If the onset is within 20 weeks of embryonic development (positive urethra, vaginal formation), the vulvar gender is blurred and becomes a female pseudohermaphroditism; after the onset of this disease, heterosexual precocity can occur after birth. In addition, adrenal adenoma or adrenal adenocarcinoma or ovarian testicular cell tumors, etc., can secrete too much androgen and cause masculinization in women.
Examine
an examination
Related inspection
Estradiol urine estradiol
The sexual maturity of menstruation, mammary gland development, pubic hair growth occurs before the age of 8 or before the standard deviation of the local average menarche age. Can be diagnosed as sexual precocity. Followed by the determination of true or pseudo precocious puberty, and looking for the cause. First of all, it is necessary to exclude diseases that are harmful to the body, such as central nervous system diseases, ovarian, adrenal tumors and other non-endocrine abnormalities caused by vaginal bleeding, such as inflammation, foreign body, trauma or genital tract tumors. When collecting medical history, it is necessary to ask whether the contraceptive is mistaken, whether the nursing mother takes the contraceptive, whether the nutrient food containing sex hormone is ingested, whether there is a history of head trauma 1 to 2 months ago, and whether there is any birth injury or convulsion. History of epilepsy and infection, whether there is a family history of precocious puberty. Understand the age of onset, the speed of disease and growth, whether there is headache or visual impairment during the course of the disease.
Pay special attention to the physical examination:
1 should record the length of the body (the ratio of the upper body to the lower body), chest circumference, arm circumference, weight, attention to the distribution of fat, the state of the body type, record the staging of sexual development and the development of external genitalia. Generally, the development of the mammary gland is equivalent to the age of 11 years old, and the menstrual cramps are equivalent to the age of 13 years old to evaluate the development of the gonads;
2 systemic examination should also pay attention to McCune-Albright syndrome, hypothyroidism, silver syndrome and other unique signs, such as skin pigmentation spots, abnormal head shape, and attention to the presence or absence of signs of nervous system abnormalities. When checking the skin, pay attention to skin pigmentation changes, acne, hair growth, excessive sebum secretion, and masculine performance;
3 abdominal, pelvic examination, pay attention to whether there is abdominal pain, abdominal mass and so on.
The disease depends on a detailed medical history, a comprehensive physical examination and necessary laboratory tests and other auxiliary examinations. At the same time, strict follow-up observation is needed to make a diagnosis of the cause. Idiopathic precocious puberty can only be diagnosed when all other diseases that can cause precocious puberty are completely excluded. During the follow-up period, special attention should be paid to the possibility of early and slow-moving subclinical intracranial tumors, and organic brain lesions. In children with precocious puberty, the endocrine changes and bone age characteristics are similar to those of idiopathic, but special examinations such as CT, MRI, EEG, EEG topography, and head X-ray may reveal abnormal signs. Symptoms and signs of intracranial organic disease occur before or after sexual development.
Diagnosis
Differential diagnosis
Differential diagnosis of female precocious puberty :
In the early stage of female precocious puberty, only the development of the mammary gland is difficult to distinguish from the premature development of the simple mammary gland. However, it is not difficult to identify it if it is followed closely. The age of precocious puberty and ovary increased significantly. The LH/FSH after GnRH stimulation was often >1. However, the size of uterus and ovary did not change in premature breast development, and LH/TSH was often <1 after stimulation. For those with early adrenal function, attention should be paid to the identification of adrenal hyperplasia and androgen-producing tumors. The former only shows pubic hair and pubic hair, and there is no other sexual development. The latter is accompanied by increased body hair, height and weight. Growth, bone age is advanced, hemorrhoids, snoring and thickening.
The sexual maturity of menstruation, mammary gland development, pubic hair growth occurs before the age of 8 or before the standard deviation of the local average menarche age. Can be diagnosed as sexual precocity. Followed by the determination of true or pseudo precocious puberty, and looking for the cause. First of all, it is necessary to exclude diseases that are harmful to the body, such as central nervous system diseases, ovarian, adrenal tumors and other non-endocrine abnormalities caused by vaginal bleeding, such as inflammation, foreign body, trauma or genital tract tumors. When collecting medical history, it is necessary to ask whether the contraceptive is mistaken, whether the nursing mother takes the contraceptive, whether the nutrient food containing sex hormone is ingested, whether there is a history of head trauma 1 to 2 months ago, and whether there is any birth injury or convulsion. History of epilepsy and infection, whether there is a family history of precocious puberty. Understand the age of onset, the speed of disease and growth, whether there is headache or visual impairment during the course of the disease.
Pay special attention to the physical examination:
1 should record the length of the body (the ratio of the upper body to the lower body), chest circumference, arm circumference, weight, attention to the distribution of fat, the state of the body type, record the staging of sexual development and the development of external genitalia. Generally, the development of the mammary gland is equivalent to the age of 11 years old, and the menstrual cramps are equivalent to the age of 13 years old to evaluate the development of the gonads;
2 systemic examination should also pay attention to McCune-Albright syndrome, hypothyroidism, silver syndrome and other unique signs, such as skin pigmentation spots, abnormal head shape, and attention to the presence or absence of signs of nervous system abnormalities. When checking the skin, pay attention to skin pigmentation changes, acne, hair growth, excessive sebum secretion, and masculine performance;
3 abdominal, pelvic examination, pay attention to whether there is abdominal pain, abdominal mass and so on.
The disease depends on a detailed medical history, a comprehensive physical examination and necessary laboratory tests and other auxiliary examinations. At the same time, strict follow-up observation is needed to make a diagnosis of the cause. Idiopathic precocious puberty can only be diagnosed when all other diseases that can cause precocious puberty are completely excluded. During the follow-up period, special attention should be paid to the possibility of early and slow-moving subclinical intracranial tumors, and organic brain lesions. In children with precocious puberty, the endocrine changes and bone age characteristics are similar to those of idiopathic, but special examinations such as CT, MRI, EEG, EEG topography, and head X-ray may reveal abnormal signs. Symptoms and signs of intracranial organic disease occur before or after sexual development.
