Delayed puberty in women

Introduction to women's puberty delay Women's puberty development is not an independent event of the reproductive system, affected by general health conditions, such as malnutrition, too thin, too fat. Because the age of puberty development is different between regions and ethnic groups, the specific age limit is difficult to determine. It is generally believed that the onset age of puberty and sexual development is more than 2.5 standard deviations behind the average age of normal children, which should be considered as delayed development of puberty. basic knowledge The proportion of sickness: 0.4% to 0.6% Susceptible people: women Mode of infection: non-infectious Complications: amenorrhea

Delayed etiology of women during puberty

(1) Causes of the disease

There are many causes of female delayed puberty, including constitutional or familial factors, hypothalamic, pituitary and gonad diseases, endocrine diseases, chromosomal abnormalities, chronic or consumptive diseases, and nutritional, mental, and psychological disorders. With sports and so on.

According to the etiology, women's puberty development delay can be divided into three categories:

1 physique (idiopathic) puberty delay;

2 low gonadotropin-induced puberty delay;

3 high gonadotropin puberty delay, hypothalamic-pituitary lesions are mostly low gonadotropin (blood FSH, LH decreased), and those involving gonads are mostly high gonadotropin (ie Blood FSH, increased LH) Delayed puberty development.

(two) pathogenesis

Hypothalamic pituitary disease

Its sexual characteristics are not developed due to hypothalamic or pituitary dysfunction, manifested as low gonadotropinic hypogonadism, which may be caused by tumors, infections, injuries or congenital defects, or may be due to other A variety of causes affect the secretion of GnRH or its pulse secretion rhythm, central nervous system tumors mainly include craniopharyngioma, pineal tumor, ectopic pineal tumor, germ cell tumor and prolactinoma, other centers Nervous system disorders may be central nervous system infections, injuries or congenital malformations, etc. There is a condition called isolated gonadotropin deficiency, patients are only gonadotropin deficiency without abnormal growth hormone or other pituitary hormones, not short Due to the low level of sex hormones, the closure of the epiphysis is slowed down, and the long bones are allowed to grow. The patient's performance is that the limbs are long, the finger distance is large, and the ratio of the upper body to the lower body is reduced.

Kallmann syndrome is a relatively common isolated gonadotropin deficiency. It is still pubertal and has no sexual development. It is often accompanied by olfactory disorders and other malformations. The disease is a heterogeneous genetic disease that can be autosomal. Sexual inheritance, autosomal recessive inheritance or X-linked inheritance, due to different genetic patterns, the types of Kallmann syndrome are diverse.

Severe systemic and chronic wasting diseases, malnutrition, etc. can cause delayed youth due to functional gonadotropin deficiency. Hypothyroidism and Cushing's disease are also often associated with delayed puberty. Anorexia is a functional promotion. Low gonadotropin, common in girls who insist on losing weight or mental stress, because they can not eat normally, leading to severe low body weight, cold, sexual development is not developed, primary amenorrhea or secondary amenorrhea, anorexia nervosa occurs in pre-puberty Leading to youth delay, some high-intensity training athletes or ballerinas, etc. due to large amount of exercise, too little fat in the body, their puberty, menarche is later than girls of the same age, pre-puberty hyperprolactinemia will occur youth delay, but more Rarely, recent studies have also suggested that drug abuse among adolescents can also lead to delays in youth.

2. Ovarian disease

Due to dysplasia or dysfunction of sexual dysfunction, due to ovarian dysfunction, unable to synthesize and secrete enough sex hormones, interfere with negative feedback regulation of pituitary and hypothalamus, increase gonadotropin secretion, leading to FSH And LH levels rise, E2 levels are low, so it is also called high gonadotropin hypogonadism, this situation is more common in congenital dysplasia and often manifested as sexual naive, there is a congenital gonadal dysplasia, also known as Turner syndrome is a congenital disease with abnormal X-number or structure. Its typical karyotype is 45, X or other variants. Children with ovarian dysplasia, lack of sex hormones and sexual traits are not developed. State, in addition, there are often a group of physical abnormalities, such as a short, neck-shaped sputum, faceted sputum, barrel chest, elbow valgus and other visceral multiple deformities, high gonadotropin hypogonadism is also seen in 46, XX and 46, XY simple gonadal dysplasia, also manifested as sexual naive, ovarian resection in early childhood or ovarian function due to radiotherapy or chemotherapy in the ovary area Ringing youthful development.

Female puberty delay prevention

Physique (idiopathic) puberty delayed patients often have a positive family history, it is recommended to do early detection and timely detection, to rule out pathological reasons, timely treatment.

Female puberty delay complications Complications amenorrhea

Women's delayed puberty temporarily affects post-marital birth, and once normal development, most people do not affect fertility as normal people, because women's puberty delays no longer exist.

Delayed symptoms of puberty in women Common symptoms Amenorrhea glandular dyslipidemia Secondary amenorrhea Pituitary dysfunction Adolescent chest development Slow fatigue Weight gain Increased intracranial pressure Hypothyroidism

1. Physique (idiopathic) puberty delay

Delayed constitutional puberty is one of the main causes of delayed development of puberty in children. These patients often have a positive family history. The mothers have delayed menarche or their fathers and siblings have a puberty delay (14-18 years old). The main reason is the activation delay of the GnRH pulse generator, which causes the hypothalamus to not produce a sufficiently strong GnRH release pulse at the age of puberty, so that the systemic gonadotropin cells cannot effectively stimulate the production of LH and FSIH, and the GnRH level is related to the patient's age. Compared with the lack of functionality, but consistent with its physiological development, adrenal cortical function and gonadal function often lag behind, which is different from single gonadotropin deficiency patients, the latter often appear in adrenal function Normal age occurs.

The patient still lacks any secondary sexual development at 13 to 16 years of age. It is characterized by short stature and childishness. It is estimated to be smaller in appearance than the actual age, but the child is completely healthy and has normal intelligence. About 60% of the children are children. His family members (especially fathers and mothers) have a similar history of late maturity. When the constitutional puberty is delayed, the body weight and height are generally normal, but the growth rate is relatively slow in the first few years after birth, accompanied by bone age maturity. Delayed, the height is often equivalent to the third percentile of the height of the child of the corresponding age or below, and the body is short throughout the child, fluctuating around the third percentile of the corresponding age, but its height is growing. The speed is close to normal, about 5cm per year. In the normal stage of growth and development of normal children, the growth of children with delayed puberty development is still slow, and the difference between them and their peers gradually expands, while the development of secondary sexual characteristics is delayed. Both height and bone age maturity are correspondingly backward (1 to 3 years), but when they reach a certain age, they will spontaneously develop secondary sexual maturity and sudden growth. At the same time, the height and bones are normal. The puberty of the child is behind the actual age, but it is consistent with the bone age. When the girl is 11 to 13 years old, the LH secretion increases during puberty, and the sleep-related nighttime LH pulse Secretion, LH secretion peak also appeared in the daytime, bone age more than 18 years old still no puberty starter, most patients can not develop puberty afterwards, but there are exceptions.

Physical examination showed that the body was short, other (including the external genitalia) were normal, and the nutritional status was good. Some children may have certain characteristics of early puberty development, such as vaginal mucosa changes, light hair growth, and sometimes even very early. The signs of puberty mammary gland development, endocrine function test and X-ray of the skull, CT and other examinations are normal, gonadotropin levels and response to GnRH are lower than the actual age and are compatible with their bone age. Plasma GH responds normally to various stimulation tests or Reduced, but returned to normal after taking low doses of sex hormones.

Baumann reports a novel short stature, a single GH deficiency secondary to the inactivating mutation of the GHRH receptor (GHRHR) gene, found in the extracellular end of the GHRHR in three unrelated families of the Indian subcontinent (E72X or E50X) The same nonsense mutation exists, and another mutation is found in the population of northeastern Brazil. It is a gene intron 1 junction mutation, and its inheritance is autosomal recessive inheritance (the gene is located on the short arm of chromosome 7) The patient is severely deficient in single GH, growth disorder after birth, and the average height of female adults is 114-130 cm. The body is well-proportioned, microcephaly, bone age and puberty are delayed, but birth is normal.

2. Low gonadotropin hypogonadism

Low gonadotropin hypogonadism (HH), manifested as delayed puberty, infertility, and low serum gonadotropin levels. The molecular mechanisms of most cases of HH are unclear, but some hypothalamic pituitary genes have been described. Single gene mutation, Kallmann syndrome is due to KAL gene (located in Xp22.3) mutation; congenital adrenal insufficiency combined with HH due to DAX1 gene (dose-sensitive reversal of the X chromosome 1 gene - congenital adrenal cortex Dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene 1) is a rare X-linked recessive genetic disease, GnRH receptor, leptin and leptin Receptor mutations can cause autosomal recessive hereditary HH. In addition, singular FSH and LH lack the HH phenotype caused by mutations in their corresponding subunit genes. Although much progress has been made, there are still about 90 The cause of HH is unknown. The clinical manifestations of this disease vary according to the age of onset of the patient, the degree of hormone deficiency, and whether or not other pituitary hormones are combined.

(1) Acquired gonadotropin deficiency: Many diseases in the brain such as intra-saddle or extra-saddle tumor, head trauma, infection, etc. cause hypothalamic and pituitary damage, and hypogonadism is often one of the manifestations of pituitary dysfunction, craniopharynx Tumors are the most common tumors that cause hypothalamic, pituitary dysfunction and sexual naivety. Patients present with headaches, visual disturbances, short stature, diabetes and limb weakness, often with abnormal fundus and visual field. In addition to low levels of sex hormones, there are other hormones involved. Such as GH, TSH, ACTH or AVP, sometimes PRL is increased, children's saddle tumors are rare, prolactinoma is a more common type of tumor in the saddle, because it can cause increased endogenous opioid peptide activity, inhibition GnRH pulse secretion, it can cause puberty development blocked, but its treatment through bromocriptine and other treatments, the condition is often improved significantly, in addition, other ectopic pineal tumors in the saddle area, mostly germ cell tumors, some patients show adolescence Does not start, symptoms of increased intracranial pressure with other symptoms of hypopituitarism, prone to diabetes insipidus, histiocytosis (Hand-Schüler-Christian syndrome) can be invaded Hypothalamic-pituitary area, showing sexual dysfunction, puberty does not start, often diabetes insipidus and other pituitary dysfunction, the disease can be manifested as a single local lesion, but also involving multiple organs, such as bone, lung, liver Etc, rare central nervous tumors still have hypothalamus or optic glioma, astrocytoma and chromoblastoma, trauma, inflammation and specific infections (such as tuberculosis) cause puberty delay is rare, manifested as gonads Patients with hypofunction are also often associated with decreased pituitary hormones. Children with arachnoid cysts may also have hypopituitarism and diabetes insipidus. For those with short stature, small hands and feet, and poor intelligence, the central nervous system lesions should be considered to cause multiple pituitary lesions. The possibility of promoting hormone deficiency.

The effect of intracranial lesions on hypothalamic-pituitary function depends on where it is located, whether there is secondary hydrocephalus and whether it has undergone surgery or radiation therapy, which can cause hypothalamic-pituitary hormone deficiency. It can also cause hypothalamic-pituitary-gonadal axis activation leading to precocious puberty.

(2) Congenital gonadotropin deficiency:

1Kallmann syndrome: a single gonadotropin deficiency, unaffected in childhood, no secondary sexual characteristics at puberty, showing a scorpion-like body type, long limbs, upper/lower <0.9, de-sexual childish In addition, it is accompanied by olfactory disorders. The study confirmed that this disease is a defect in a gene located in Xp22.3 (KAL gene). GnRH cells in the olfactory substrate migrate to the brain during embryonic stage, and the patient's LH pulse is defective in secretion. Gonadal dysplasia or no development.

2 congenital adrenal insufficiency combined with gonadotropin deficiency: the main cause of puberty age is the lack of gonadotropin, but the disease is mostly due to the lack of glucocorticoids and mineralocorticoid deficiency, if not replaced in time Treatment is likely to survive less than the age of puberty. According to the scope of gene deletion, patients may also have Duchenn muscle atrophy, glycerol kinase deficiency, ornithine carboxyformyltransferase deficiency and mental retardation. Exogenous GnRH pulse therapy is effective.

3 simple gonadotropin deficiency: caused by hypothyroidism in gonadotropin, no abnormal body, treatment with gonadotropin can make gonadal function normal.

4PraderWilli syndrome is characterized by obvious obesity, shortness, sexual naivety and mental retardation. There are also characteristics of low muscle tone, small hands and feet, and amygdoid appearance in infants. About half of the patients are accompanied by the long arm of chromosome 15. Deletion (Del 15q11-12), almost all patients have a father-derived chromosome 15 deletion.

5Laurence-Moon-Biedl syndrome mainly manifests as obesity, short stature, multi-finger malformation, retinitis pigmentosa, mental retardation and hypogonadotrophic gonadal dysfunction, an autosomal recessive disorder, retinopathy of patients It is progressively aggravated until blindness. About 15% of children aged 5 to 10 years have retinal pigmentation, and 73% are blind at 20 years of age. Obesity often begins in early childhood.

(3) Idiopathic pituitary short stature often causes hypopituitarism due to hypothalamic release hormone deficiency, first manifested as short stature and then expressive naive, short stature is an early manifestation, unlike patients with single GH deficiency, the latter does not need to Exogenous steroid sex hormone therapy can also develop puberty when the bone age reaches 11 to 13 years old, and the skeletal age of this patient after GH treatment will not start puberty, and it is effective by sex hormone replacement therapy.

(4) Functional gonadotropin deficiency systemic metabolic disorder, malnutrition or mental factors, strenuous exercise can lead to low secretion of gonadotropin, unable to initiate functional activity of the gonadal axis, when the above factors are removed, hypothalamic-pituitary-gonadal The functional activity of the shaft will return to normal. It is believed that when the weight drops below 80% of normal, it often leads to gonadotropin secretion dysfunction, sexual development or developmental stagnation, strengthening nutrition, making weight gain and maintaining the hypothalamus after a period of time - Pituitary-gonadal axis function can be restored. Common diseases include anorexia nervosa, diabetes, necrotic enteritis, etc. In recent years, it has been suggested that leptin plays an important role in regulating neuroendocrine changes during starvation. Decreased blood leptin concentration, weight loss, initiation of some neuroendocrine reactions including decreased secretion of thyroid hormone, increased secretion of stress hormone (ACTH, cortisone), low gonadotropin hypogonadism, delayed ovulation, hypothalamic neuropeptide Y (NPY) mRNA expression is enhanced, fertility is reduced, and thyroid can be obtained after intraperitoneal administration of recombinant human leptin Hormone is elevated, stress hormones are reduced to normal, NPY is reduced to normal, and ovulation is normal. Leptin acts as a puberty initiation signal related to metabolism and feeding, acting on the hypothalamus, accelerating puberty initiation and reproductive function, Abima et al. It is believed that the mechanism of accelerated maturation of leptin has two aspects. One is that leptin directly acts on GnRH neurons, induces pulse secretion or accelerates GnRH mRNA expression; and second, it may be mediated by other factors (such as NPY, -aminobutyric acid). , glutamic acid, etc., of which the more research is the relationship between leptin and NPY.

Chronic renal failure and its treatment can interfere with puberty initiation and development, including pathways including endocrine, metabolic and neuropsychological abnormalities and drug effects. Even children with renal failure, even if they have a kidney transplant, are delayed by an average of 2 years, in addition to their growth. Not as high as healthy children, blood diseases such as sickle cell anemia, thalassemia, bone marrow transplantation, etc., can cause hypothalamic and/or pituitary damage leading to insufficient GH secretion, sexual dysfunction, hypothyroidism, showing growth and sexuality Delayed development.

The changes of endocrine hormones in patients with anorexia nervosa are more complicated. The levels of LH, FSH and estradiol are lower. In severe cases, the LH pulse frequency is reduced, the pulse amplitude is decreased, and the body weight is lower than 75% of the ideal body weight. After a single GnRH stimulation. LH reaction is not obvious or disappears, continuous vein GnRH (frequency is 90-120min) stimulation, LH pulse response is the same as normal puberty, indicating that amenorrhea in patients with anorexia nervosa is mainly due to functional GnRH deficiency, strenuous exercise causing puberty delay and amenorrhea Inhibition of hypothalamic GnRH pulse generator, resulting in insufficient secretion of gonadotropin, is not related to weight loss, this effect may be partly mediated by the endogenous opioid peptide pathway, normal body weight fat, large amount of women Athletes and ballerinas have delayed puberty, and the incidence of primary and secondary amenorrhea is high. Even if the weight does not change significantly after several months of cessation of exercise, puberty initiation and menarche may occur.

Cystic fibrosis (CF) is a common disease affecting Caucasians in North-West Europe. It can cause malnutrition and delayed growth and development. The latter is the result of delayed maturity of the hypothalamic-pituitary-gonadal axis due to malnutrition. Studies have shown that in patients with cystic fibrosis, the synthesis of steroid hormones and thyroid hormones is affected, thyrotropin stimulates the uptake and excretion of iodine to synthesize thyroid hormones, and gonadotropins also stimulate the transport of chloride ions in Leydig cells to synthesize steroid sex hormones. The primary defect causing CF is a transmembrane conductance regulator (CFTR) mutation, which is a slow channel present in the "apical membrane of wet epithelia" due to these hormones. The synthesis may be related to CFTR, and it is believed that part of the reason for the delayed growth of CF is the defect of hormone synthesis.

3. High gonadotropin hypogonadism Most patients are caused by genetic factors such as gonadal differentiation and dysplasia, such as Turner syndrome karyotype 45, XO or its variant, female appearance, short stature, sexual naive, Mammary gland is not developed, primary amenorrhea, often accompanied by physical malformations, simple gonadal dysplasia is also common, karyotype 46, XX, 46, XY, other causes of high gonadotropin-type puberty delay are less common, adolescence Former girls with chemotherapy or pelvic radiotherapy for other diseases can cause delayed development of puberty. In addition, autoimmune ovarian inflammation, caused by ovarian failure, primary amenorrhea, rare menstruation or puberty development, etc., ovarian resistance is a rare Primary hypogonadism, abnormal PSH and LH receptors, elevated blood FSH, LH levels, other diseases caused by 17-hydroxylase deficiency leading to sex hormone synthesis disorders, galactosemia is very rare.

Female puberty delayed examination

Laboratory inspection:

1. Blood, urine routine, erythrocyte sedimentation rate, liver and kidney function tests can be used to understand the whole body condition, blood sugar, urine sugar, liver and kidney function, etc. if necessary.

2. Endocrine hormone determination mainly measures gonadotropin (FSH, LH) and sex hormones (estradiol, testosterone), determination of estradiol level can understand the functional status of the ovary, when E2>33.03pmol/L (9pg/ml), It is generally believed that there is adolescent functional activity, but E2 often has fluctuations that cannot be used as a basis for diagnosis. LH secretion increases during normal puberty at night, so the measurement of nighttime LH is more diagnostic. GnRH stimulation test is used to identify constitutional and pathological puberty. Delay, identification of pituitary or hypothalamic lesions have important value. Under normal circumstances, after intravenous injection of GnRH, subjects have age-adapted plasma LH and FSH responses in patients with primary sexual insufficiency and Turner syndrome. The response is enhanced, the hypothalamic and pituitary dysfunction is reduced, and the responsiveness of constitutional puberty is compatible with its bone age.

When the whole pituitary function is low, the GH level is low, but when the GH is slightly lower than the normal level, the constitutional puberty delay cannot be excluded, because the delayed GH level in the constitutional puberty is often slightly lower than normal, and the two may overlap, T3, T4, TSH. Determine the presence or absence of hypothyroidism, determine the adrenal function if necessary, and see if adrenal function is present.

Other auxiliary inspections:

1. X-ray examination of the wrist flatness determination of bone age should be listed as a routine examination, because the correlation between puberty initiation and bone age is significantly related to its actual age, head X-ray examination, craniopharyngioma mostly have abnormal saddle area, And 70% present calcification, so lateral plain film examination can help diagnose.

2. B-ultrasound can understand the size, shape and uterus development of the ovary, and also help the diagnosis of other abdominal diseases.

3. CT and MRI examination CT and MRI have important diagnostic value for central nervous system tumors.

4. Chromosome examination For gonad hypoplasia or some special facial signs often prompted karyotype analysis.

5. Laparoscopy and gonadal biopsy for suspected ovarian lesions (such as ovarian dysplasia or tumor), if necessary, laparoscopic and gonad biopsy can be adapted.

When the whole pituitary function is low, the GH level is low, but when the GH is slightly lower than the normal level, the constitutional puberty delay cannot be excluded, because the delayed GH level in the constitutional puberty is often slightly lower than normal, and the two may overlap, T3, T4, TSH. Determine the presence or absence of hypothyroidism, determine the adrenal function if necessary, and see if adrenal function is present.

Female puberty delayed diagnosis

diagnosis

At present, the standard accepted by most scholars is 13 to 13.5 years old. There is no mammary gland development, no pubic hair growth at 15 years old, and no menarche at 18 years old. It can be diagnosed as delayed puberty.

Physical puberty delay must rule out the diagnosis of various pathological causes, such as patients with the following characteristics can be diagnosed as physical puberty delay:

1 The growth and development rate in childhood is basically normal, and after the age of puberty, there is developmental backwardness, and the maturity of the bone age is delayed accordingly;

2 The development of secondary sexual characteristics is later than the standard deviation of 2 to 2.5 standard deviations at the onset of normal children's sexual development;

3 has a similar family history;

4 no abnormal medical history, normal physical examination, laboratory screening test is normal;

5 When the bone age of the child is close to the normal developmental age of puberty, spontaneous development and growth spurt, the GnRH stimulation test is of great value in the differential diagnosis of constitutional and pathological youth delay.

Differential diagnosis

The diagnosis process of puberty delay is actually a process to determine the cause. First, the constitutional and pathological puberty delay should be identified. The typical ones are not difficult to distinguish according to their clinical characteristics, but some cases must undergo strict follow-up observation and a series of examinations. Identification, female puberty delays are often identified with primary amenorrhea.

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