Idiopathic hypogonadotropic hypogonadism

Introduction to idiopathic hypogonadotropin hypogonadism Low gonadotropin hypogonadism (HH) includes a large group of diseases, congenital GnRH neuronal defects, pituitary gonadotropin deficiency or molecular structural abnormalities, chronic systemic diseases, mental stress, severe weight loss or long-term strenuous exercise Both can cause gonadotropin deficiency. In addition, gonadotropin deficiency is also a component of some congenital syndromes (such as Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, etc.). The degree of gonadotropin deficiency is also heterogeneous. One extreme is completely adolescent sexual maturity, the other extreme is puberty delay, and the middle is a different degree of excessive type. basic knowledge The proportion of illness: 0.005% Susceptible people: no specific population Mode of infection: non-infectious complication:

Idiopathic hypogonadotropin hypogonadism

(1) Causes of the disease

The genetic characteristics of IHH are not a single type in the family analysis data, and there are at least three different genetic approaches.

The results of some family analysis found that a father with olfactory loss had a son with olfactory dysfunction and/or hypogonadism, and his daughter had normal gonad development and olfactory. A more interesting example is that the father is a Kalman syndrome patient. After long-term treatment with human chorionic gonadotropin, they married and gave birth to sons suffering from Kalman syndrome. These families are consistent with autosomal dominant inheritance, while others are ancestors and fathers. In the third generation of children, both males and females have olfactory dysfunction and hypogonadism. This genetic pattern is clearly consistent with autosomal recessive inheritance. In addition, some family fathers are normal, mothers are carriers, and children are born. Only males have hypogonadism and/or olfactory loss. After the daughter gets married, the female offspring of the female are normal, while the male offspring are patients with Kalman syndrome, which belongs to X-linked inheritance. This genetic heterogeneity Not only in the genetic way, but even in the same genetic pattern, there is heterogeneity in expression, that is, the same family Among the members, there may be simple hypogonadism without olfactory loss, or only olfactory loss and no hypogonadism; the degree of olfactory loss is also different, and the olfactory loss of some affected family members is incomplete, only the sense of smell is reduced, one A more prominent example is a pair of 20-year-old identical twin brothers, one of whom is a typical Kalman syndrome patient, while the other has only a olfactory loss, normal reproductive organs, and normal levels of plasma gonadotropin and testosterone.

(two) pathogenesis

The molecular genetic basis of the X-linked genetic Kalman syndrome has been determined. The terminal part of the short arm of the X chromosome is a pseudo-autosomal region. The DNA sequence of this segment is homologous to the pseudo-autosomal region of the Y chromosome. When splitting, DNA segmentation and exchange occur in this segment of the X and Y chromosomes. The genes in the pseudo-autosomal region are double doses in both sexes, thus avoiding the inactivation of the X chromosome. This segment contains PHOX/SHOX ( Short stature) gene, MI C2 (a cell surface antigen) gene, punctate dysplasia gene, intelligent decline gene, STS (steroid sulfatase) gene and KAL1 (Kalman syndrome) gene, using gene mapping technology It can be confirmed that the KAL1 gene is located in the Xp22.3 region, close to the STS gene. In patients with X-linked Kalman syndrome, large or small deletions, point mutations and various nonsense mutations have been found in the KAL1 gene, resulting in structural changes. And a premature stop codon, a few patients found no mutations in the cryptodomain, the mutation may be in the promoter region, the loss of adjacent genes may cause Kalman syndrome, X-linked fish (STS gene deletion), hypothermia and/or punctate dysplasia, different mutations in the KAL1 gene transcribe different gene products, the latter is related to the heterogeneity of clinical manifestations, and now can be applied Southern blotting technology Analysis of fetal DNA in prenatal diagnosis of X-linked Kalman syndrome, KAL1 gene length of about 1.5Mb, encoding a 680 amino acid glycoprotein, functionally this protein has the characteristics of extracellular neural adhesion molecules, may be GnRH Neurons migrate from the olfactory plate at the fetal stage to the guide protein at the medial base of the hypothalamus. There is currently no feasible protocol for gene therapy, but the structure of the KAL1 gene and its encoded protein has been elucidated. One day, gene therapy is used to supplement normal structural proteins to prevent it. Kalman syndrome is not completely impossible. As for the autosomal dominant and recessive inheritance, the two types of pathogenic genes are still poorly known. Is there a gene similar to KAL1 in an autosome? Or is the KAL1 gene also associated with autosomal inheritance? In addition, simple expression of low gonadotropin hypogonadism Whether patients without impaired sense of smell also is KAL1 gene plays a key role? These issues needs further study to answer.

The GnRH receptor (GnRH-R) gene has been cloned and located on the long arm of chromosome 4, a G protein-coupled membrane receptor with 7 transmembrane regions, N-terminally outside the cell, but no cells At the C-terminus, activation of the receptor increases phosphatase activity and promotes G-protein-mediated intracellular calcium mobilization. Recently, a family has reported a case of IHH caused by GnRH-R mutation. Patient male, 22 years old, smell Normal, no other malformations, no beard, pubic Tanner stage III, penis length 6cm, testicular volume 8ml, semen analysis sperm density 3.91×106/ml, 43% normal morphology, 5% activity, fructose and citrate concentration Significantly lower than normal, serum testosterone level 2.8nmol / L, LH4.OU / L, FSH5.9U / L, LH and FSH response to GnRH (100g) stimulation test, LH8h pulse analysis (1 time per 10min) The pulse frequency is normal, the pulse amplitude is reduced (only 1/5 of the normal pulse amplitude), the patient's eldest sister is 14 years old, puberty starts, primary amenorrhea and infertility, B-ultrasound found bilateral ovaries small, no dominant follicles, patients Parents and second sisters have normal sexual development, 3 exon DNA of GnRH-R gene Sequencing of the amplified product revealed that the patient and his older sister had two complex heterozygous mutations. One was the Gln106Arg mutation in the first loop of the recipient cell, and the adenine forming the nucleotide 317 was replaced by guanine; the second was the cell. The Arg262Gln mutation in the 3rd loop makes the 785 nucleotide guanine replaced by adenine, the mother only carries the Gln106Arg mutation, the father and the patient's second sister only carry the Arg262Gln mutation, and the extracellular 1st loop of GnRH-R The binding ability of the receptor is related. The experimental Asn102Ala mutation completely disables the ability of GnRH-R to bind to GnRH. The Gln106Arg mutation still preserves some biological reactions, which may be caused by the relative instability of the receptor hormone complex, GnRH-R. The third loop in the cell is a key region of receptor signaling. The Arg262G1n mutation does not affect the binding of the receptor to the hormone, but affects the post-receptor reaction such as G protein coupling and receptor internalization.

GnRH gene deletion has successfully demonstrated low gonadotropin hypogonadism in experimental studies in mice, suggesting that GnRH gene mutation is one of the causes of IHH, but GnRH gene sequencing in a small number of IHH patients has not been found. Abnormalities such as deletions or point mutations.

In order to study and understand the secretory mode and characteristics of GnRH in the hypothalamus, the following two methods are generally adopted: First, the peripheral blood is frequently collected from normal people to measure LH and/or FSH, and the pulse frequency and amplitude are analyzed, according to each GnRH described above. Pulse can induce the principle of 1 LH (and FSH) secretion pulse. The pulse frequency of LH must be reflected by the pulse frequency of GnRH. The amplitude of LH pulse is the result of the combination of the release of each GnRH pulse and the feedback of sex hormone feedback. The second is to study the GnRH secretion pattern in IHH patients or animal models, which is very important for understanding the mechanism of GnRH pulse secretion and formulating exogenous GnRH replacement therapy. When performing pulse analysis, it should be recognized: 1 although each Both LH and FSH pulses are reflections of GnRH pulses, but not every GnRH pulse is transcribed by the pituitary to recognizable LH and FSH pulses, ie the number of LH and FSH pulses is not necessarily exactly equal to the number of pulses of GnRH; LH and FSH pulses should be observable. If some data is lost, the analysis of pulse frequency and amplitude may be inaccurate; 3 affect pulse analysis The factors include the sensitivity of the hormone determination method, the method of determining the pulse and the blood collection density. The most influential factor is the blood collection density. The blood collection density is closely related to the length of the pulse interval. The optimum blood collection density is 5 to 10 minutes.

According to the commonly used radioimmunoassay method, the coincidence rate of LH pulse frequency and GnRH pulse is higher than that of FSH pulse. This is because FSH has a longer half-life, different secretion modes of LH and FSH, and sex hormones, statins, actin and follicles. Inhibitory proteins are regulated by two gonadotropins. For example, testosterone levels in adult men or E2 levels in women's mid-follicles have greater inhibition of FSH than LH, and changes in pulse frequency of GnRH can change the proportion of LH/FSH release. Etc., the normal adult male LH pulse interval is about 90 ~ 120min, that is, 12 ~ 16 pulses appear in 24h, the normal adult male LH pulse frequency has quite a variation, 24h only 7 pulses still have normal sexual development and fertility Examples of abilities have been reported. The normal adult woman's LH interpulse has a significant menstrual cycle. The early follicles (2 to 6 days of menstruation) are about 100 minutes, the pulse amplitude is moderate, and the pulse release during sleep almost completely stops. (7th to 10th day of menstruation) is about 60min, the pulse amplitude is reduced, there is a pulse during sleep, and the late follicle (11th to 14th day of menstruation) is about 70min, pulse amplitude Increased degree, no difference between day and night pulse, early luteal phase (1st to 4th day of ovulation) is about 100min, large pulse (amplitude >15U/L) and small pulse (<5U/L) coexist, middle luteal phase (ovulation 5th to 9d) ) is about 200min, small pulse accounts for 50%, late luteal phase (10th to 14th ovulation) is about 300min, and large pulse is reduced to 1-2/24h, almost all of which are small pulses.

There is several abnormalities in LH pulse secretion in male IHH patients (at least once every 10 minutes): 1 no pulse secretion, as in prepubertal children, this type of secretion is most common in IHH male patients, accounting for 75% of all cases, 2 nights of pulse secretion, similar to the situation in early childhood initiation of puberty, these patients often have a history of puberty initiation, testicular relatively large, but later stagnation, failed to complete the puberty development process, it is also known as Adolescent stagnant type, 3 pulse amplitude is low, this small pulse is not enough to stimulate the synthesis and secretion of testosterone in the testis, the 4 pulse frequency is insufficient, 24 hours less than 7 pulses, the secretion of testosterone can reach 21.0mmol / L in the pulse However, with the disappearance of LH pulse, serum testosterone levels gradually decrease, can not maintain the normal range, can not maintain the development of reproductive organs and secondary sexual characteristics, see Figure 1, LH pulse secretion abnormalities in female IHH or hypothalamic amenorrhea patients and The same as seen in male IHH patients, can also be divided into no pulse type, adolescent stagnant type, pulse amplitude reduction type and pulse frequency Abnormal secretion slows down mode type four kinds.

Idiopathic hypogonadotropin hypogonadism prevention

1. Regular examinations of the breast, gynecology, and cardiovascular systems should be performed during estrogen replacement therapy.

2. Sex hormone replacement therapy dose should start from a small amount to avoid premature closure of the epiphysis leading to short stature.

Idiopathic hypogonadotropin hypogonadism complications Complication

Idiopathic low gonadotropin hypogonadism symptoms Common symptoms Coffee spot green blind bone age delay youth risk period beard sparse olfactory loss adolescent chest development slow bow foot ataxia

IHH patients before the puberty, such as no small penis, cryptorchidism or other organs or physical abnormalities, are generally not easy to find, most patients because of the adolescent age asexual development and seek medical treatment, a small number of patients have started adolescence, but stagnation in the middle, sexual The maturity process was not completed as scheduled. These patients had a larger testicular volume and reached the level of puberty stage II or III. About 90% of patients had small larynx, pubic hair and pubic hair, and a small number of patients had a small amount of pubic hair growth (Tanner In pubic hair stage II), 80% of patients have bone age behind the actual age, 40% have olfactory loss or olfactory loss, 20% have men's mammary gland hyperplasia, may have small penis, cryptorchidism and vas deferens are absent, and may be accompanied by other bodies or Organ abnormalities, such as facial midline malformations: rabbit lips, cleft palate, sacral arch high tip and short tongue ligament, abnormal nervous system: neurological deafness, eye movement or abnormal vision, red-green blindness, cerebellar ataxia, hand and foot joint movement and Epilepsy, abnormal musculoskeletal system: osteoporosis, rib fusion, 4th metacarpal short, phalanx long and arched foot, other system abnormalities: skin milk coffee Spots, renal hypoplasia or malformation, congenital cardiovascular disease (aortic arch right position, subclavian artery stenosis, atrioventricular block and right ventricular hypertrophy, etc.), usually of normal height, a small number of patients with short stature, obesity, general intelligence is normal.

The clinical manifestations of IHH are related to the type of abnormal GnRH pulse secretion in the hypothalamus. The clinical manifestations of male IHH patients and the results of LH pulse analysis can be found that patients without pulse secretion can be divided into two parts: the first part has the most cases Heavier condition, never had spontaneous puberty development, testicular small, average volume is about 3ml, testicular biopsy histology is the same as prepubertal children, often accompanied by olfactory loss or olfactory hypothesis, the average serum LH level is 1.7 ±0.3 U / L, FSH 2.1 ± 0.2 U / L, a small number of patients with LH and FSH reduced below the detectable range, may have cryptorchidism and penis small, the second part of the patient is less, about this type of patient 23%, the condition is mild, there is incomplete spontaneous puberty development, stagnation in the middle, testicular size, volume up to 3 ~ 8ml, testicular biopsy showed no spermatogenesis, mature stagnation or even normal spermatogenesis, The sense of smell is normal, there is no cryptorchidism and small penis, but the average level of serum LH and FSH is not significantly different from that of the first part of the patient. Adolescent stagnant patients have LH pulse points at night. Secret, at the age of 14 to 15 years of age, has a certain degree of sexual maturity, testicular volume of up to 8 ~ 12ml, may have spontaneous penile erection and sexual impulses, but sexual development can not continue, stay in In the early stage of puberty, there is no olfactory loss or decline, serum LH and FSH levels can reach the lower limit of the normal range on average, the test volume of the pulse amplitude reduction type is 3-6 ml, the serum testosterone level is 1.1-3.5 nmol/L, and the LH and FSH levels are low. In normal, patients with pulse frequency slowing down due to testosterone secretion during pulse, serum testosterone levels fluctuate between 3.8 ~ 21.0mmol / L, there is a certain degree of sexual development, testicular volume can reach 10 ~ 15ml, no olfactory loss There may be men's breast hyperplasia, which is the mildest type of IHH.

Examination of idiopathic hypogonadotropin hypogonadism

1. Serum sex hormone levels are lower than normal, and LH and FSH levels are normally lower or lower than normal.

2. GnRH Excitatory Test Whether in male or female patients, the secretion response of LH is generally reduced, and a few patients have no response or normal response at all. The LH response of the same patient may be inconsistent with the FSH reaction.

3. The basal level of serum PRL is normal. The response of PRL to thyrotropin releasing hormone (TRH) and chlorpromazine stimulation test is generally normal, a small number of reactions are reduced, and individual reactions are too strong.

4. The patient's thyroid function (clinical manifestations and TT4, TT3, FT4, FT3 and TSH) were normal. The TRH-excited TSH test generally responded normally. The circadian rhythm of ACTH and cortisol was normal, and cortisol responded normally to ACTH excitation.

5. Urine concentration function is normal.

The above data indicate that in addition to the hypothalamic-pituitary-gonadal axis, the PRL, GH, ACTH and TSH of the pituitary gland function normally, and the function of the neurohypophysis is normal.

1. Patients with a positive family history should undergo autosomal examinations as much as possible for family analysis.

2. Check the sense of smell, red, green blindness, etc.

Diagnosis and differentiation of idiopathic hypogonadotropin hypogonadism

diagnosis

The diagnosis of IHH is quite difficult. For patients with suspected IHH, detailed medical history should be collected to understand the growth and development of intrauterine and juvenile, and whether there is growth stagnation. Generally speaking, the growth stagnation of IHH is relatively light, and the height is basically The normal height of children of the same age is within the range of normal height. However, due to the long-term low level of sex hormones, patients who have passed the puberty age have overgrown limbs and form a test-free type (lower amount > upper volume, finger distance > height), with a positive family history. Patients should conduct family analysis as much as possible. There are currently three proven inheritance methods: X-linked, leucotoxic and autosomal dominant. The possibility of other genetic methods cannot be ruled out. Physical examination should specifically check the sense of smell. Patients with olfactory loss or olfactory dysfunction are more serious. Some patients may have red, green blind, cleft palate and/or mid-line developmental deformities such as the labrum. Other developmental abnormalities can be found in the central nervous system, bones and kidneys, and intelligence is normal. The penis is small, the testicles may be incomplete, and there is no sign of sexual development after puberty, and the bone age lags behind the actual Age, adrenal cortical function is now starting at 6 to 8 years old, serum gonadotropin and sex hormones are still at a low level before puberty, GH levels are normal, when the clinical performance and experimental examination are still insufficient to determine the diagnosis, it needs long-term Following the observation, generally 18 years old as a boundary, more than 18 years old still no puberty starter can be diagnosed as IHH.

Differential diagnosis

Mainly idiopathic puberty delay, idiopathic puberty delayed growth retardation, bone age behind the actual age, sexual naivety, low serum gonadotropin and sex hormone levels, and gonadotropin no response or reduced response to GnRH excitation Very similar to IHH, it is difficult to identify each other. Many scholars have done a lot of research over the years, trying to find a differential diagnosis test to effectively distinguish these two situations. These experiments are briefly introduced as follows.

1. Chlorpromazine excited PRL test

The rationale for this trial is that chlorpromazine antagonizes the release of dopamine from dopaminergic neurons in the hypothalamus, thereby abolishing the inhibition of pituitary prolactin cells by dopamine and increasing the secretion of PRL. IHH patients are often not a single GnRH secretion defect. There may also be abnormalities in other aspects of the hypothalamus (including regulation of PRL secretion). In addition, sex hormones may alter the reactivity of pituitary prolactin cells to dopamine inhibition and promote the synthesis and release of PRL. The test should be 8-9 am. The chlorpromazine dose was 0.33 mg/kg intramuscularly, and the PRL was measured at -15, 0, 15, 30, 45, 60, and 90 min in the forearm vein, respectively. The serum PRL peak was found in early adolescence and normal adult men. 15g/L, untreated IHH patients <5g/L, PRL peaks in IHH patients treated with HCG or testosterone for 6 months reached the level of normal adult men.

2. Metoclopramide excited PRL test

The trade name of metoclopramide is metoclopramide or metoclopramide, which is a dopamine blocker that significantly stimulates the release of PRL. The adverse reaction is lighter than chlorpromazine. The dose is 10mg/m2 or 2.5mg. Intravenous bolus injection at 8-9 am, PRL was measured in the forearm at -15, 0, 15, 30, 45, 60 and 90 min, respectively. The result was a significant overlap between serum PRL peaks in idiopathic puberty delay and IHH. Or can't be distinguished.

3. Thyroid stimulating hormone releasing hormone (TRH) excited PRL test

TRH is a PRL releasing factor. There is a TRH receptor on the cell membrane of pituitary prolactin, which can bind to TRH and stimulate the secretion of PRL. The test method is fasting overnight. The venous channel is established at 8 am, and a single intravenous bolus injection of TRH 5 g/ Kg, the maximum dose does not exceed 200g, PRL is measured in the forearm at -15,0,15,30,45,60 and 90min, respectively, and the peak of PRL is used to judge the idiopathic puberty and normal adult men>22g/ L, IHH patients <22g / L.

4.36h GnRH stimulation before and after GnRH stimulation test GnRH 100g single intravenous bolus injection, LH and/or FSH were measured at -15, 0, 15, 30, 45, 60 and 90 min, respectively, and delayed LH response in idiopathic puberty The peak height was higher than IHH, but there was overlap of 45%. There was no difference between the two groups in the FSH peak. Then, 5 g of GnRH was injected subcutaneously every 90 min by pulse pump for 36 h, and then the GnRH 100 g single dose excitatory test was repeated. The result was the peak of LH in the second excitatory test. The idiopathic puberty delay group was 5 times higher than the IHH group. The absolute value of peak height was >3 U/L in the idiopathic puberty delay group, 3 U/L in the IHH group, and the FSH/LH ratio idiopathic puberty delay group. <0.55, IHH>0.55.

5. GnRH agonist stimulation test

At 8 o'clock on the first day of the test, the forearm blood was collected for LH, FSH and testosterone. At 4 o'clock in the morning, subcutaneous injection of tryptorelin 0.1 g/m2 was given. After 4 h (8 o'clock on the second day), blood was collected again to measure LH. FSH and testosterone, the peak of LH in the delayed puberty group increased by 20U/L, the FSH increased by 10U/L, and the testosterone increased by 3 times; the peak of LH in the IHH group increased by 3U/L, the FSH increased by 2U/L, and the testosterone did not. Variety.

6. Determination of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS)

DHEA and DHEAS are markers of adrenal cortex function. In normal children, plasma DHEA and DHEAS begin to increase about 2 years before puberty (about 6-8 years old), while other adrenal corticosteroid levels do not change. Known as the adrenal cortex function, the elevation of DHEA and DHEAS levels peaked at 20 to 30 years old, and then gradually decreased. The adrenal cortical function of children with delayed idiopathic puberty was delayed, and IHH patients occurred as scheduled. Children over the age of 6 years, by measuring plasma DHEA and DHEAS levels, it is possible to identify these two cases, that is, IHH patients with DHEA and DHEAS levels significantly higher than idiopathic puberty delay.

7. Testosterone determination

Determination of serum testosterone at 8 am also contributes to idiopathic puberty delay and IHH identification. If the testosterone level at 8 am is >0.7 nmol/L, it suggests that the testicle begins to increase within 15 months (>4 ml). Predicting that adolescence initiation will occur, the patient is likely to be delayed in idiopathic puberty.

In the above differential diagnosis test, except for the metoclopramide test, other methods of identification suggest that there is a difference between idiopathic puberty delay and IHH patients, and statistically significant differences are significant or significant, however, most The measured values of the test were very close in the idiopathic puberty delay group and the IHH group, and the reliability or specificity of the identification point was poor. In addition, the number of cases was small, and the feasibility of the test still required a large number of cases.

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