Delayed puberty in females

　　1. Etiology

　　There are many causes of delayed puberty in females (femaledelayedpuberty), including constitutional or familial factors, hypothalamic, pituitary, and gonadal diseases, endocrine diseases, chromosomal abnormalities, systemic chronic or consumptive diseases, as well as nutritional, mental, psychological disorders, and exercise, etc.

　　According to the characteristics of the etiology, the delayed puberty of female development can be divided into 3 categories:

　　1. Constitutional (idiopathic) delayed puberty.

　　2. Delayed puberty with low gonadotropin levels.

　　3. Delayed puberty with high gonadotropin levels. The lesions caused by hypothalamic-pituitary disorders are mostly hypogonadotropic (blood FSH, LH decreased), while the lesions involving the gonads are mostly hypergonadotropic (i.e., blood FSH, LH increased), leading to delayed puberty development.

　　2. Pathogenesis

　　1. Hypothalamic-pituitary disease

　　The underdevelopment of the characteristics is caused by hypothalamic or pituitary dysfunction, manifesting as hypogonadotropic hypogonadism. This dysfunction can be caused by tumors, infections, injuries, or congenital defects, and may also be due to various other reasons affecting the secretion amount or pulsatile secretion rhythm of GnRH. Central nervous system tumors mainly include craniopharyngioma, pinealoma, ectopic pinealoma, germ cell tumors, and prolactinoma, etc. Other central nervous system diseases may include central nervous system infections, injuries, or congenital malformations, etc. There is a condition called isolated gonadotropin deficiency, where the patient only lacks gonadotropins without any abnormalities in growth hormone or other pituitary hormones. Due to the low level of sex hormones, the closure of epiphyses is slowed down, allowing for the growth of long bones. Patients are characterized by long limbs, wide finger span, and a reduced proportion of the upper body to the lower body.

　　Kallmann syndrome is a relatively common isolated gonadotropin deficiency. At the age of puberty, there is still no development of sexual characteristics, often accompanied by olfactory disorders and other anomalies. The disease is a non-homogeneous genetic disease, which can be autosomal dominant inheritance, autosomal recessive inheritance, or X-linked inheritance. Due to different genetic modes, Kallmann syndrome has various types.

　　Severe systemic and chronic consumptive diseases, malnutrition, and other factors can lead to delayed puberty due to a lack of functional gonadotropins. Hypothyroidism and Cushing's disease are also often associated with delayed puberty. Anorexia nervosa is a functional hypogonadotropic condition commonly seen in girls who are determined to lose weight or are anxious. Due to the inability to eat normally, it leads to severe low body weight, aversion to cold, underdeveloped sexual characteristics, primary amenorrhea, or secondary amenorrhea. Anorexia nervosa if occurs in the prepubertal period can lead to delayed puberty. Some high-intensity athletes or ballet dancers and others due to large amounts of exercise and low body fat, their pubertal development and menarche are later than girls of the same age. High prolactinemia before puberty can cause delayed puberty, but it is relatively rare. Recent research also suggests that drug abuse among adolescents can also lead to delayed puberty.

　　2. Ovarian diseases

　　Dysgenesis of sexual characteristics due to incomplete development or dysfunction of the ovaries. Due to low ovarian function, it cannot synthesize and secrete sufficient sex hormones, which interferes with the negative feedback regulation of the pituitary and hypothalamus, leading to increased secretion of gonadotropins, elevated levels of FSH and LH, and low levels of E2. Therefore, it is also known as hypergonadotropic hypogonadism. This condition is often seen in congenital developmental abnormalities and is often manifested as sexual immaturity. There is a congenital gonadal dysgenesis, also known as Turner syndrome, which is a congenital disease with abnormal number or structure of the X chromosome. Its typical karyotype is 45, X or other variant forms. The affected children, due to the underdeveloped ovaries, lack of sex hormones, and underdeveloped sexual characteristics, present in a state of sexual immaturity. In addition, there are often a group of somatic abnormalities, such as short stature, webbed neck, multiple freckles, barrel chest, genu varum, and multiple visceral malformations. Hypergonadotropic hypogonadism is also seen in 46, XX and 46, XY simple gonadal dysgenesis, which also manifests as sexual immaturity. The removal of the ovaries during childhood or damage to ovarian function due to radiotherapy or chemotherapy in the ovarian area can affect pubertal development.

　　Delayed puberty in women can temporarily affect post-marital fertility, but once normal development occurs, most people are unaffected by fertility like normal individuals. This is because delayed puberty in women no longer exists. In addition to low sex hormones, other hormones are also affected, such as GH, TSH, ACTH, or AVP, and sometimes PRL is increased. Children with intrasellar tumors are rare, and prolactinoma is a relatively common type of intrasellar tumor.

　　1. Constitutional (idiopathic) delayed puberty

　　Constitutional delayed puberty is one of the main reasons for delayed puberty in children. Such patients often have a positive family history, with many mothers having delayed menarche or fathers and siblings having a history of delayed puberty (14-18 years old). It is believed that the main reason is the delayed activation of the GnRH pulse generator, causing the hypothalamus to not produce enough strong GnRH release pulses at the age of puberty, resulting in the inability of the gonadotropin cells in the body to effectively stimulate the production of LH and FSH. The level of GnRH is functionally deficient compared to the patient's age, but consistent with their physiological development. The initial appearance of adrenal cortex function and gonadal function is often behind, which is different from patients with single gonadotropin deficiency, where adrenal function often appears at a normal age.

　　Patients still lack any secondary sexual characteristics between the ages of 13 to 16, characterized by short stature, immature appearance, and estimated to be younger than their actual age. However, the children are completely healthy, with normal intelligence. About 60% of children have a family history of similar delayed puberty, especially with the father, mother, or siblings. The children with constitutional delayed puberty are generally born with normal weight and height, but their growth and development are relatively slow in the first few years of life, accompanied by delayed bone age maturation. Their height is often at the third percentile or below the corresponding age of children. Throughout the childhood, they have short stature, fluctuating around the third percentile of the corresponding age. However, their growth rate is close to normal, about 5cm per year. At the age when normal children experience a sudden growth spurt, children with constitutional delayed puberty still have slow growth and development, and the differences with their peers gradually increase. At the same time, their height and bone age maturity are also correspondingly behind (1-3 years), but when they reach a certain age, second sexual characteristics will spontaneously appear with a sudden increase in height, and their height and bones will also reach normal. The onset of puberty in these patients is behind their actual age, but often consistent with their bone age. Girls may experience an increase in LH secretion during puberty at the age of 11 to 13, initially related to sleep-related nocturnal LH pulse secretion, and later, LH secretion peaks also appear during the day. Those with bone age over 18 years old without the onset of puberty will not be able to develop puberty in most cases, but there are exceptions.

　　Physical examination shows that in addition to short stature, other aspects (including external genitalia) are normal, nutrition status is good, some children may appear some characteristics of early puberty development, such as changes in vaginal mucosa, growth of light-colored hair, and sometimes even very early signs of breast development during puberty can be shown, endocrine function tests and cranial X-ray, CT and other examinations are normal, the level of gonadotropin and the response to GnRH are lower than the actual age but appropriate to the bone age, the response of plasma GH to various stimulation tests is normal or decreased, but after intake of low-dose sex hormones, it returns to normal.

　　Baumann reported a new type of dwarfism, which is a single GH deficiency secondary to an inactive mutation in the GHRH receptor (GHRHR) gene. An identical nonsense mutation (E72X or E50X) in the extracellular domain of GHRHR was found in the extracellular domain of three unrelated families in the Indian subcontinent, and another mutation was found in the northeastern population of Brazil, which is an intronic junction mutation, and its genetic mode is autosomal recessive (gene located on the short arm of chromosome 7), the patient has a severe single GH deficiency, growth disorders after birth, the average adult height of women is 114-130 cm, with a proportional figure, microcephaly, delayed bone age and puberty development, but normal fertility.

　　Second, hypogonadotropic hypogonadism

　　Hypogonadotropic hypogonadism (HH), characterized by delayed puberty, infertility, low serum gonadotropin levels, the molecular mechanism of most HH cases is still unclear, but certain single gene mutations of hypothalamic-pituitary genes have been described, Kallmann syndrome is due to mutation of the KAL gene (located at Xp22.3); Congenital adrenal cortical hypoplasia associated with HH is caused by mutation of the DAX1 gene (the dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene 1), which is a rare X-linked recessive genetic disease, mutations in the GnRH receptor, leptin, and leptin receptor can cause autosomal recessive HH, in addition, the HH phenotype with single FSH and LH deficiency is caused by mutation of the corresponding beta subunit gene, although great progress has been made, but still about 90% of HH reasons are unknown, the clinical manifestations of this disease vary according to the age of onset, the degree of hormone deficiency, and whether other pituitary hormone deficiencies are associated.

　　1. Acquired gonadotropin deficiency

     Many intracranial diseases such as intrasellar or parasellar tumors, cranial trauma, infections, etc., can cause hypothalamic and pituitary damage, hypogonadism, which is often one of the manifestations of hypopituitarism. Craniopharyngioma is the most common tumor leading to hypothalamic and pituitary dysfunction and hypogonadism, with patients presenting with headaches, visual disturbances, short stature, diabetes, and limb weakness. There are often abnormalities in fundus and visual field, in addition to low sex hormones, other hormones are also affected, such as GH, TSH, ACTH, or AVP, and sometimes PRL is elevated. Intranasal tumors in children are rare, prolactinoma is a common type of intranasal tumor. Due to its ability to increase endogenous opiate peptide activity and inhibit GnRH pulsatile secretion, it can cause delayed puberty development. However, its condition often significantly improves through treatments such as bromocriptine. In addition, other ectopic pinealomas in the sellar region are mostly germinoma, some patients present with delayed puberty, symptoms of increased intracranial pressure accompanied by other hypopituitarism symptoms, prone to diabetes insipidus. Hand-Schüler-Christian syndrome can erode the hypothalamic-pituitary region, with manifestations of decreased sexual function, delayed puberty, and often diabetes insipidus and other hypopituitarism. The disease can manifest as a single local lesion or involve multiple organs such as bones, lungs, and liver. Rarer central nervous system tumors include hypothalamic or optic nerve gliomas, astrocytomas, and chromophobe adenomas. Trauma, inflammation, and specific infections (such as tuberculosis) that cause delayed puberty are rare, and those with hypogonadism often have other pituitary hormones decreased. Children with arachnoid cysts may also appear with hypopituitarism and diabetes insipidus. For those with short stature, small hands and feet, and poor intelligence, it is necessary to consider the possibility of central nervous system lesions leading to multiple pituitary trophic hormone deficiencies.

　　The effect of intracranial lesions on the hypothalamus-pituitary function depends on their location, the presence of secondary hydrocephalus, and whether they have received surgical or radiation therapy. These lesions can cause both a deficiency of hypothalamus-pituitary hormones and activation of the hypothalamus-pituitary-gonadal axis, leading to precocious puberty.

　　2. Congenital gonadotropin deficiency

　　(1) Kallmann syndrome: It is characterized by a single gonadotropin deficiency. Physical development during childhood is not affected, and there is no appearance of secondary sexual characteristics during puberty, manifesting as a eunuchoid body type, long limbs, and an upper/lower body segment ratio of less than 0.9. In addition to hypogonadism, there are also olfactory disorders. Research has confirmed that this condition is caused by a defective gene (KAL gene) located at Xp22.3. The GnRH cells in the olfactory plate migrate to the brain abnormally during embryogenesis, leading to a defect in LH pulsatile secretion in patients, resulting in poor or no gonadal development.

　　(2) Congenital adrenal皮质hypoplasia combined with gonadotropin deficiency: The main reason for the failure to develop during puberty in patients with this disease is the lack of gonadotropins. However, most children with this disease have a deficiency of glucocorticoids and mineralocorticoids due to combined deficiency, and they may not survive to reach the age of puberty without timely replacement therapy. Depending on the range of gene deletion, patients may also have Duchenne muscular dystrophy, deficiency of glycerol kinase, deficiency of ornithine carbamoyltransferase, and intellectual disability, etc. Exogenous GnRH pulse therapy is effective.

　　(3) Congenital gonadotropin deficiency: Hypogonadism is caused by low gonadotropin levels, without any abnormal stature. Treatment with gonadotropins can restore normal gonadal function.

　　(4) Prader-Willi syndrome is primarily characterized by marked obesity, short stature, hypogonadism, and intellectual disability. It also has features such as low muscle tone in infancy, small hands and feet, and a double-amygdala facial appearance. About half of the patients have an interstitial deletion of the long arm of chromosome 15 (Del15q11-12), and almost all patients have a deletion of chromosome 15 from the father.

　　(5) Laurence-Moon-Biedl syndrome is primarily characterized by obesity, short stature, polydactyly, pigmentary retinopathy, intellectual disability, and hypogonadotropic hypogonadism, which is an autosomal recessive genetic disease. The retinal lesions in patients are progressive and may lead to blindness. Approximately 15% of children aged 5 to 10 years have retinal pigment deposition, and 73% are blind by the age of 20. Obesity often begins in early childhood.

　　3. Idiopathic pituitary dwarfism

     Commonly caused by defects in hypothalamic releasing hormone, leading to hypopituitarism, initially manifested as short stature followed by sexual immaturity. Short stature is an early manifestation, and is different from patients with single GH deficiency, who can appear puberty development when the bone age reaches 11-13 years old even without exogenous steroid sex hormone treatment. However, in patients with this disease, puberty will not start even after GH treatment when the bone age reaches this level, and sexual hormone replacement therapy is effective.

　　4. Functional gonadotropin deficiency

     Obvious metabolic disorders, malnutrition, or mental factors, as well as intense exercise, can lead to low secretion of gonadotropin, which prevents the initiation of the functional activity of the gonadal axis. When the aforementioned factors are removed, the functional activity of the hypothalamus-pituitary-gonadal axis will return to normal. It is believed that weight loss to below 80% of normal often leads to dysfunction of gonadotropin secretion, incomplete sexual development, or development arrest. Strengthening nutrition, increasing and maintaining weight for a period of time, can restore the function of the hypothalamus-pituitary-gonadal axis. Common diseases include anorexia nervosa, diabetes, necrotizing enterocolitis, etc. Recent research suggests that leptin plays an important role in regulating neuroendocrine changes during hunger. After 48 hours of fasting, mice show a decrease in blood leptin concentration, weight loss, and the initiation of some neuroendocrine responses including reduced thyroid hormone secretion, increased secretion of stress hormones (ACTH, cortisol), hypogonadotropic hypogonadism, delayed ovulation, enhanced mRNA expression of hypothalamic neuropeptide Y (NPY), decreased reproductive capacity. After intraperitoneal administration of recombinant human leptin, thyroid hormone levels increase, stress hormones decrease to normal, NPY decreases to normal, and normal ovulation occurs. Leptin, as a puberty initiation signal related to metabolism and eating, acts on the hypothalamus to accelerate the initiation of puberty and the emergence of reproductive function. Abima et al. believe that the mechanism by which leptin accelerates sexual maturation has two aspects: one is that leptin directly acts on GnRH neurons, inducing their pulsatile secretion or accelerating GnRH mRNA expression; the other is that it may be mediated by other factors (such as NPY, gamma-aminobutyric acid, glutamate, etc.), among which the relationship between leptin and NPY has been studied extensively.

　　Chronic renal failure and its treatment can interfere with the initiation and development of puberty, involving pathways such as endocrine, metabolic, and neuropsychological abnormalities as well as drug effects. Even after renal transplantation, the onset of puberty in children with renal failure is delayed on average by 2 years, and in addition, their growth height is also less than that of 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, incomplete sexual function, hypothyroidism, and showing delayed growth and sexual development.

　　The endocrine hormone changes in anorexia nervosa patients are complex, with low levels of LH, FSH, and estradiol. In severe cases, the frequency of LH pulses decreases and the amplitude decreases. In patients with body weight below 75% of the ideal weight, the LH response after a single GnRH stimulation is not obvious or disappears. Continuous intravenous GnRH stimulation (frequency of 90-120 min) results in LH pulse responses similar to those in normal puberty, indicating that the amenorrhea in anorexia nervosa patients is mainly due to functional GnRH deficiency. Delayed puberty and amenorrhea caused by intense exercise is due to the suppression of the hypothalamic GnRH pulse generator, resulting in insufficient gonadotropin secretion, which is not related to weight loss. This effect may be partly mediated by the endogenous opioid peptide pathway. Female athletes with low body fat and high levels of exercise, such as ballet dancers, experience delayed puberty and a higher incidence of primary and secondary amenorrhea. Even if there is no significant change in body weight after stopping exercise for a few months, there will be the onset of puberty and the first menstruation.

　　Cystic fibrosis (cysticfibrosis, CF) is a common disease affecting white people in northwestern Europe, which can lead to malnutrition and delayed growth and development. The latter is the result of delayed maturation of the hypothalamus-pituitary-gonadal axis due to malnutrition. Recent studies have shown that the synthesis of steroid hormones and thyroid hormones is affected in cystic fibrosis patients. Thyroid-stimulating hormone 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, causing the primary defect in CF is the mutation of the transmembrane conductance regulator (transmembrane conductance regulator, CFTR), which is a slow channel existing on the apical membrane of 'wet' epithelia. Since the synthesis of these hormones may be related to CFTR, it is believed that part of the delayed growth and development in CF is due to a defect in hormone synthesis.

　　Three, Hypogonadotropic Hypogonadism

　　Most patients have sexual gland differentiation and development abnormalities caused by genetic factors, such as Turner syndrome with karyotype 45, XO or its variants, presenting with female appearance, short stature, sexual immaturity, undeveloped breasts, primary amenorrhea, and often accompanied by physical malformations. Simple gonadal dysgenesis is also common. Karyotypes 46, XX, 46, XY, and other causes leading to delayed puberty with high gonadotropin levels are less common. Girls before puberty may experience delayed puberty development due to chemotherapy or pelvic radiation for other diseases. In addition, autoimmune ovarianitis, primary amenorrhea due to ovarian dysfunction, oligomenorrhea, or cessation of puberty development, ovarian resistance is a rare primary gonadal dysfunction, patients have abnormal PSH and LH receptors, elevated blood FSH and LH levels, and other causes include 17α-hydroxylase deficiency leading to disorders in sex hormone synthesis, and galactosemia is very rare.

　　Patients with constitutional (idiopathic) delayed puberty often have a positive family history. It is recommended to do relevant examinations early to detect them in time, exclude pathological causes, and treat them in time. Some girls dislike their small breasts and take estrogen to promote breast development. Although there is a temporary effect, over time, it will increase the possibility of breast, vagina, cervix, uterine body, and ovarian cancer. The abuse of estrogen is not only easy to cause nausea, vomiting, and anorexia, but also lead to uterine bleeding, uterine hypertrophy, menstrual irregularity, and liver and kidney dysfunction.

　　First, laboratory examination

　　1. Routine blood and urine tests, erythrocyte sedimentation rate, liver and kidney function tests can understand the general condition of the body, and glucose, urine sugar, liver and kidney function tests are measured when necessary.

　　2. Endocrine hormone measurements mainly determine gonadotropins (FSH, LH) and sex hormones (estradiol, testosterone). Measuring estradiol levels can understand the functional status of the ovary. When E2 is above 33.03 pmol/L (9 pg/ml), it is generally considered that there is pubertal functional activity, but E2 often fluctuates and cannot be used as the sole basis for diagnosis. Normally, the increase in LH secretion at night during the initiation of puberty makes the measurement of nocturnal LH more valuable for diagnosis. The GnRH stimulation test is of great value in distinguishing constitutional and pathological delayed puberty, and in distinguishing pituitary or hypothalamic lesions. Normally, after intravenous injection of GnRH, the test subjects show a plasma LH and FSH response appropriate to their age. In patients with primary sexual dysfunction and Turner syndrome, the response is enhanced, the hypothalamic and pituitary function is reduced, and in patients with constitutional delayed puberty, the reactivity is appropriate to their bone age.

　　When the entire pituitary function is low, GH levels are low, but when GH is slightly lower than the normal level, constitutional delayed puberty cannot be ruled out, as the GH level in constitutional delayed puberty is often slightly lower than the normal level, and there may be overlap between the two. T3, T4, and TSH tests are used to determine whether there is hypothyroidism. If necessary, the adrenal cortex function status should be measured to determine whether there is an early appearance of adrenal function.

　　Other auxiliary examinations

　　1. X-ray examination of wrist flat film should be listed as a routine examination to determine bone age, as the correlation between the onset of puberty and bone age is more obvious than its correlation with actual age. Cranial X-ray examination shows that craniopharyngiomas mostly have鞍区abnormalities, and 70% show calcification, so lateral flat film examination can assist in diagnosis.

　　2. Ultrasound examination can understand the size, shape, and development of the uterus, and also help in the diagnosis of other abdominal lesions.

　　3. CT and MRI scans have important diagnostic value for tumors in the central nervous system.

　　4. Chromosome examination often suggests the need for karyotype analysis for those with incomplete gonadal development or certain special facial features.

　　5. Laparoscopic examination and gonadal biopsy should be performed for those suspected of having ovarian lesions (such as underdeveloped ovaries or tumors), and laparoscopic examination and gonadal biopsy can be performed as necessary.

　　When the entire pituitary function is low, GH levels are low, but when GH is slightly lower than the normal level, constitutional delayed puberty cannot be ruled out, as the GH level in constitutional delayed puberty is often slightly lower than the normal level, and there may be overlap between the two. T3, T4, and TSH tests are used to determine whether there is hypothyroidism. If necessary, the adrenal cortex function status should be measured to determine whether there is an early appearance of adrenal function.

　　Diet should be light and nutritious, with attention to dietary balance. Avoid spicy and stimulating foods. In order to avoid recurrence of the disease, such as seafood, chicken, dog meat, and so on. At the same time, do not ban stimulating foods. Eat more fresh vegetables and fruits. Fresh vegetables and fruits contain a large number of nutrients needed by the human body. Eat more foods that enhance immunity to improve the body's ability to resist diseases.

　　First, treatment

　　The treatment of delayed puberty in women mainly depends on the cause and nature of the disease.

　　1. Constitutional delayed puberty

     Since the children with this disease will eventually enter puberty, general treatment is not required, but necessary counseling should be provided to alleviate the concerns and worries of children and parents, eliminate feelings of inferiority, and regularly evaluate the development of the child's sexual characteristics and perform relevant hormone tests. If some children experience mental stress due to their development lagging behind their peers, or even abnormal mental, psychological, and behavioral disorders, appropriate medication may be administered as necessary, using short-term hormone therapy to stimulate the appearance of sexual characteristics. Before medication, it is necessary to explain in detail to the children and their families the expected goals of the medication and possible side effects, and try to allow the children and parents to make their own choice between medication and continued observation. Girls can take 5 to 10 mg of ethinyl estradiol orallyμ. 0.3 to 0.625 mg/d of conjugated estrogens (equine estrogens) for 3 to 6 months, and regular checks of the patient's sexual characteristics and physical development. After treatment, especially when the bone age reaches 13 to 14 years, puberty will spontaneously start. Otherwise, pathological reasons should be considered.

　　2. Pathological delayed puberty

　　(1) Eliminating the cause: The main treatment is based on the cause, such as surgical removal of tumors, active treatment of systemic diseases, and improvement of nutritional status. Once the cause is eliminated, the symptoms can be relieved; for those with unremovable causes, hormone replacement therapy should be applied. For patients with high gonadotropin levels, the cause is often unremovable, and hormone replacement therapy is mainly used to promote sexual development, menstruation, or growth. However, for those with Y chromosomes in the karyotype, gonadectomy should be performed. For patients with functional hypogonadotropic hypogonadism, as the delayed puberty is secondary to other diseases, the principle is to treat the primary disease, strengthen nutrition, improve weight, or adjust the amount and method of exercise. These patients do not need exogenous hormone treatment, and sexual development will spontaneously occur after the above conditions improve.

　　(2) Hormone Replacement Therapy: Whether estrogen therapy accelerates epiphyseal closure is a common concern. It has now been clarified that only androgens in supraphysiological doses have this effect. Generally, diethylstilbestrol 5μ. g/d has no effect on the closure of the epiphyses and has a mild effect on promoting the growth of long bones. Long-term use can slightly develop the breasts. For patients with primary hypogonadism, long-term hormone replacement therapy is required, starting with a low dose, similar to the treatment method for constitutional delayed puberty, and gradually increasing to the adult replacement dose after 2 to 3 years to simulate the hormone levels after the normal onset of puberty. The initial dose is ethinyl estradiol 5μ. g/d or combined estrogen (equilin) 0.3mg/d. Gradually increase to ethinyl estradiol 10 to 25mg/d in the following 2 to 3 years.μ. g/d or combined estrogen (equilin) 0.6 to 1.25mg/d, the maintenance dose should be able to achieve withdrawal bleeding. Withdrawal bleeding or starting treatment within the first 6 months, starting from the 12th day of oral estrogen, gestagens (such as medroxyprogesterone 5mg/d) should be added.

　　Patients with low gonadotropin hormone levels can also choose exogenous (GnRH pulse pump therapy, which is more similar to physiological GnRH secretion, involving subcutaneous or intravenous catheterization. GnRH (10 peptide) is injected once every 60 to 120 minutes, with a dose of 25ng/kg. Most patients can complete sexual development and have ovulation after 1 to 2 years of treatment. Due to the high cost, this method is not suitable for long-term treatment and can be used for those who wish to have children. If the patient still has GH deficiency, GH treatment can be ideal before the epiphyses close, based on the estimated growth potential of the patient's height.

　　II. Prognosis

　　For the treatment of hypogonadotropic hypogonadism, estrogen replacement therapy can only be used. Estrogen supplementation can promote the development of secondary sexual characteristics and, when combined with gestagens, can have a periodic uterine bleeding similar to menstruation. Generally, there is no hope of fertility, unless assisted reproductive technology using donor eggs is used. For individuals with incomplete gonadal development due to the presence of the Y chromosome, as there is a high risk of malignant tumors in these gonads, gonadectomy should be performed as soon as possible, followed by estrogen replacement therapy.

　　Patients with bone age over 18 years old who have not yet entered puberty, except for a few exceptions, most patients cannot have pubertal development.