Growth hormone deficiency (GHD) is due to the anterior pituitary synthesis and secretion of human growth hormone (growthhormone, GH) partial or complete lack of, or due to structural abnormalities, such as receptor defects caused by the growth and development of the disorder.Its height is normal, healthy children of the same age, and sex growth curve under the third percentile or less than two standard deviations, short stature (shortstature) standard.With its incidence of 20/10 ~ 25/10.
[ Growth hormone synthesis, secretion and function ]

Human growth hormone (hGH) is a single chain polypeptide is synthesized and secreted by the anterior pituitary cells , 191 amino acids with a molecular weight of 22KD, genes coding GHl at 17q22-24. In the blood circulation , and about 50% of growth hormone GH binding protein (GHBP) combined to form GH-GHBP complex exists. Release of human growth hormone secreted by the hypothalamus two neurohormones that growth hormone releasing hormone (GHRH) and somatostatin (somatostatin, SRIH or GHIH) regulation. GHRH is a 44 amino acid residues containing a polypeptide , promote the synthesis and secretion of pituitary GH secreting cells GH; SRIH cyclic peptide structure 14 depress the secretion of a variety of GH secretagogues . In the interaction between these two pituitary peptide pulsed way to release hGH, and the central nervous system through dopamine, 5 – serotonin and norepinephrine neurotransmitters regulate the secretion of hypothalamic GHRH and SRIH .

HGH can play a direct role in cell biological effects , but most of its functions must like growth factor (insutin-likegrowthfactor, IGF) mediated by insulin. The human body has two IGF, IGF-I and that IGF-Ⅱ. IGF-I is a single chain polypeptide having a molecular weight 7.5KD , which gene is located 12q22-24.1, secreting cells are widely present in the liver, kidney, lung, heart, intestine and brain tissues , mainly by the synthetic hGH adjustment , and also age, nutrition and hormone levels and other factors. Synthesis of IGF-I secretion mostly in an autocrine manner or neighbor to play its role in promoting growth . The role of IGF-Ⅱ has not been elucidated . Circulating hGH concentration and IGF- workers can feedback regulation of pituitary hGH secretion , inhibit the secretion of GHRH or indirect effects on the hypothalamus , and stimulate SRIH secretion. Under the combined effect of various factors , hGH secretion was pulsatile nature , occur about every two hours a peak high secretion after falling asleep at night , and with the depth of sleep ; daytime fasting and after exercise occasionally peak. Babies born high serum GH levels , secretion rhythm is not yet mature , so sleep – wake cycle GH levels rarely fluctuate. 2 to 3 weeks after birth , serum GH concentrations began to decrease , the secretion rhythm began to appear after birth two months. Children of daily GH secretion than adults, higher secretion at puberty .

The basic function of serono serostim hGH is to promote growth in vivo is also an important regulator of metabolic pathways regulate many metabolic substances . ① growth-promoting effects: the promotion of human cells in various tissues increases and proliferation, bone, muscle and organ growth and development of each system , bone growth that causes the body to grow taller. ② promote metabolic effects : on the basis of growth-promoting effect of hGH is anabolic , can promote protein synthesis and amino acid transport and uptake ; promote glycogen breakdown and reduce glucose utilization , reduce the sensitivity of cells to insulin , so hyperglycemia ; promoting fat tissue decomposition and oxidation of free fatty acids during ketogenic ; promote chondrocyte proliferation and synthesis of bone matrix contains collagen and sulfated glycosaminoglycans. [ Cause ]
Growth hormone deficiency is due to inadequate secretion of hGH , for the following reasons :

1 . Idiopathic ( primary ) of such children in the hypothalamus , pituitary no obvious lesions, but the lack of GH secretion , and its cause is unknown. Which due to neurotransmitters – neurohormonal pathways function defects , leading to inadequate secretion of GHRH short stature caused by hormone called neuroendocrine dysfunction (GHND). Since GHD hypothalamic dysfunction caused by pituitary insufficiency leading to much higher than those of many.

About 5% of children with GHD caused by genetic factors , known as hereditary human growth hormone deficiency (HGHD). Human growth hormone gene cluster is encoded by the gene GHl (GH-N) and CSHPl, CSHl, GH2, CSH2 about 55Kbp genes composed of DNA strands . Due to the lack of GHl gene called simple growth hormone deficiency (1GHD), and by the pituitary transcription factor Pit-1 caused by the defect , the clinical manifestations of multiple pituitary hormone deficiency , known as the Joint pituitary hormone deficiency (CPHD) . IGHD according to the mode of inheritance is divided into I (AR), Ⅱ (AD), Ⅲ (X linked ) III . In addition , there are a small number of children with short stature due to GH molecular structural abnormalities , GH receptor deficiency (Laron syndrome ) or IGF receptor-deficient ( African Pygmy people ) caused similar clinical symptoms and GHD , but showed resistance to GH or IGF- I resist , serum GH levels are not reduced or increased but is relatively rare genetic disease.

2 . Organic ( acquired ) secondary to hypothalamic , pituitary or other intracranial tumors , infection, cell infiltration, radiation injury and head trauma , including birth trauma is the main cause of domestic GHD ‘s . In addition, pituitary abnormalities, such as agenesis , hypoplasia or empty sella , some accompanied by visual septum hypoplasia (Septo-opticdysplasia), cleft lip , cleft palate and other deformities , can cause the synthesis and secretion of growth hormone disorders .

3 . Temporary growth delay puberty physical , social psychological growth inhibition, primary hypothyroidism , etc. can cause temporary GH secretion dysfunction in external adverse factors eliminate or primary disease can be restored to normal after treatment. [ Clinical manifestations ]
Idiopathic growth hormone deficiency is more common in boys , male: female = 3:1. When the height and weight of children born were normal , appeared to slow down the growth rate after 1 year of age , height, weight behind the more serious lower than the height is lower than the same age , same sex normal healthy child growth curve of the third percentile or less ( or less than two standard deviations ) , height annual growth rate of less than 4cm, mental development is normal. Children with head round, childish face , chubby face , delicate skin , hair, slim , poor jaw and chin growth, delayed tooth eruption and irregular arrangement . Although the growth of children behind, but well-proportioned body parts , in line with their actual age . Skeletal retardation, bone age lagged behind the actual age of 2 years old, the same age but its height . Epiphyseal fusion of late. Most of delayed puberty .

Part of the growth hormone deficiency in children accompanied by one or more other pituitary hormone deficiency , growth retardation in addition to these children , there are other associated symptoms : accompanied by adrenocorticotropic hormone (ACTH) deficiency is easy to hypoglycemia ; with thyroid stimulating hormone (TSH) deficiency may have loss of appetite, do not love activities mild thyroid deficiency symptoms ; gonadotropin deficiency associated with gonadal dysgenesis , appear small penis ( ie straighten penis length of less than 2.5cm ) , the adolescent still no sexual organs and secondary sexual characteristics and so on.

Organic growth hormone deficiency can occur at any age , in which the cause of perinatal abnormalities who often accompanied by diabetes insipidus -like . Alarming is intracranial tumors are more than a headache, vomiting, visual field defects , increased intracranial pressure and optic nerve oppressed signs and symptoms.

[ Laboratory ]
1 . Growth hormone stimulation test growth hormone deficiency diagnosis relies GH determination . Normal serum GH value is very low , and showed pulsatile secretion , affected by various factors , the random blood test for the diagnosis of GH blood does not make sense , but if any blood GH levels were significantly higher than normal (> 10 ~ g / L) , can be ruled out GHD. Therefore , GHD children suspected GH stimulation test must be done to determine the function of the pituitary GH secretion . Determination of GH secretion function tests commonly used are shown in Table 17-1.
Department of Physiology test screening test , drug test for the confirmatory test . Generally believed that during the test , GH peak <10ug / L is not normal secretory function . GH peak <5ug / L, the complete lack of GH ; GH peak 5 ~ 10ug / L, a lack of GH section. Due to various GH stimulation test have certain limitations , be two or more drugs to stimulate the test results are not normal, be diagnosed with GHD. More generally choose clonidine or insulin plus levodopa test . For younger children , especially when fasting insulin hypoglycemia were to be especially careful , because it can lead to hypoglycemia, seizures and other serious reactions. In addition, housekeeping is the difference between the lesion in the hypothalamus or pituitary GHRH stimulation test to be done .

17-1 secretion of growth hormone blood test Test Methods Table physiological one time . Sports fasting for 4 – 8 hours after strenuous activity 15 – 20 minutes after the start activity 20 – 40 minutes 2 . When night sleep after sleep EEG monitoring with Ⅲ ~ Ⅳ sleep drugs to stimulate a . Insulin 0.05–0.1U/kg, intravenous 0,15,30,60,90,120 minutes to measure blood sugar , GH,

2. Arginine
0.05/kg, paired with water for injection 5% to 10 % solution , finished 30 minutes 0,30,60,90,120 min infusion measured GH3. Clonidine 0.004mg/kg, 1 oral ditto 4. Levodopa 10mg/kg, 1 oral ditto

2 . The 24h blood GH normal GH secretion spectroscopy very different peak values ​​of the base , GH secretion 24h to compare accurately reflect the in vivo GH secretion , especially for children GHND their secretion of GH stimulation tests for drug normal , but the amount is less than 24h secretion , GH peak during sleep at night is also low . However, this method tedious , blood more often, difficult for patients to accept.

3 . Insulin-like growth factor (1GF-1) measured IGF-1 mainly in the form of protein binding (1GF-BPs) is present in the blood circulation , which IGF-BP3 mainly ( over 95%), IGF-BP3 have transport and regulation IGF-1 function , and its synthesis is also regulated by GH-IGF axis , so IGF-1 and IGFBP3 are indicators of the axis detection function . Both GH secretion patterns with different , non- pulsatile secretion was less fluctuation in day and night , so very stable , its concentration is very low in children under 5 years of age , and the age and developmental changes in the larger , reached the peak of puberty , girls than men children reached a peak two years earlier . It is generally available as a 5 -year-old children before puberty GHD screening to detect . The index has some limitations , but also by nutritional status, degree of development and the impact of thyroid functional status and other factors, should determine the outcome attention.

4 . Other laboratory examinations
(1) X -ray examination : common pieces left wrist metacarpal and phalangeal bone age assessment . GHD in children 2 years of age or bone age lags behind the actual age of 2 years and older .
(2) CT or MRI : children have been diagnosed with GHD choose cranial CT or MRI needed to understand the hypothalamic – pituitary or without organic disease, especially cancer is important. 5. Other endocrine examination GHD once established, must check the hypothalamic – pituitary axis other features. Clinical manifestations can choose measured according TSH, Ding 4 or thyrotropin-releasing hormone (TRH) stimulation test and luteinizing hormone releasing hormone (LHRH) stimulation test to determine the hypothalamic – pituitary – thyroid axis and gonadal axis function .

[ Diagnosis and differential diagnosis ]

1 . The diagnosis diagnosis based on: ① short stature, tall behind the same age , and the third percentile for children of the same sex to normal ; ② slow growth, the growth rate of <4cm / years ; ③ behind the actual bone age more than 2 years of age ; ④ GH stimulation test shows partial or complete lack of GH ; ⑤ normal intelligence , commensurate with age ; ⑥ rule out other diseases affected.

2 . The reason behind the growth differential diagnosis caused a lot , to be identified with GHD are:
( 1 ) familial short stature : tall parents are short, tall children often left in the third percentile , but its annual growth rate of more than 4cm / years , bone age and age-appropriate , smart and normal sexual development .
( 2 ) physical sexual delayed puberty : the temporary GHD in the most representative of this disease , is a variation of normal development , more common in boys. Puberty began to develop later time than normal children 3-5 years of slow growth before puberty , bone age corresponding backward, but the height is consistent with bone age after puberty its final height is normal. One of the parents often have a history of delayed puberty .
( 3 ) congenital ovarian dysgenesis (Turner syndrome ) : a girl with short stature should be considered disease. The clinical features of Turner syndrome are: short stature, no development of secondary sexual characteristics , short neck, webbed neck , elbow valgus, the low hairline . A typical Turner syndrome and GHD difficult to distinguish , but the arm of chromosome mosaicism or equal to those caused by atypical symptoms due , karyotype analysis should be conducted to identify .
( 4 ) congenital hypothyroidism : the disease except for growth retardation , basal metabolic rate, bone age lagged behind , there are mental retardation , it is difficult to distinguish with GHD . But some obvious symptoms of late-onset cases , reduce the need to rely on blood T4 , TSH increased identification.
( 5 ) skeletal disorders : a variety of bone, cartilage hypoplasia , have a special face and body , with optional bone X-ray examination to identify.
( 6 ) the growth of other endocrine and metabolic diseases caused by backward : congenital adrenal hyperplasia , precocious puberty, Cushing’s syndrome , each with its clinical manifestations mucopolysaccharidosis , glycogen storage disease , is easy to identify.

[ Treatment ]

1. The growth hormone gene recombinant human growth hormone (rhGH) recombinationhGH, replacement therapy has been widely used, which are largely 0.1 U/kg;Daily subcutaneous injection before sleeping, 6-7 times a week.Treatment should be continued until the epiphyseal healing.Treatment age is smaller, the better the results, the effect is best, in the first year annual growth can reach more than 10 cm, after growth rate gradually decreases.Can appear in the process of treatment with rhGH thyroxine deficiency, we must monitor thyroid function, if there is a lack of appropriate and treated with thyroxine and at the same time.

RhGH treatment side effects are less, basically have: (1) local injection redness, associated with rhGH preparation insufficient purity as well as individual reaction, can be disappeared after drug withdrawal;(2) a few months after injection of antibodies, but had no significant effect on the growth effect;(3) a rare side effects are temporary papillary edema, intracranial pressure, etc.;(4) in addition to study found that increasing the incidence of the epiphyseal sliding out and necrosis of the femoral head, but the risk is relatively low.

Malignant tumor or potential tumor progression, severe diabetic patients disabled rhGH.

2. The growth hormone releasing hormone (GHRH)
Are now known to many GH lacks subordinate the thalamus, the application of GHRH can work, has good curative effect to the GHND, but lack of pituitary GH is invalid.Average daily dosage of 8 ~ t ~ 30 g/kg, every day sooner or later one subcutaneously or 24 h continuous subcutaneous micro pump injection.

3. Oral sex hormone of anabolic steroids are (1) fluoride hydroxyl methyl testosterone (Fluoxymesterlone) 2.5 mg/m2 per day, (2) hydrogen oxygen a dragon (Oxandvolone) 0.1 0.25 mg/kg every day, and (3) pyrazole methyl hydrogen dragon 0.05 mg/kg per day, are the derivatives of androgen, its synthetic metabolism is strong, the role of androgen is weak, has accelerated skeletal maturity and masculine side effects occur, reason should be the strict observation of bone development.Benzyl propionate nandrolone (Durabolin) has been less application.

At the same time with GHD of gonad axis dysfunction children at the age of 12 the bone age to start treatment with sex hormone and male long-term heptanoic acid injectable testosterone 25 mg, once a month, 25 mg per 3 month, until a month l00mg;Women can use ethinylestradiol 1 ~ 2 ug/day, or pregnant mare estrone (Joshua) since 0.3 mg daily discretionary increase gradually, at the same time to monitor bone age