Neuroprotective effects of growth hormone

Growth hormone is a single-chain polypeptide with 191 amino acids that primarily controls various physiological processes such as growth and metabolism. Cell membrane receptors that bind growth hormone to target cells, such as adipocytes and chondrocytes, directly stimulate proliferation. In addition, growth hormone can act indirectly through the synthesis of insulin-like growth factor-1 in the liver and target tissues. Insulin-like growth factor-1 actually exerts a growth promoting effect on a wide range of tissues and leads to the growth of bone and muscle. With regard to metabolic regulation, growth hormone promotes protein anabolism, mobilizing storage of triglycerides, hepatic glucose production and insulin resistance.
Professor Manho Kim of Seoul National University Hospital in Seoul, China, published a paper in the 8th issue of the Chinese Journal of Neuroregeneration Research (English Edition) in August 2015. The signal transduction pathway, the physiological function in the brain, focuses on juvetrope human growth hormone in the muscle. Therapeutic potential and therapeutic effects in atrophic lateral sclerosis.

The effect of hormones on blood sugar

Experimental principle
• There are two types of hormones involved in blood glucose regulation: one is a hormone that lowers blood sugar, only one is insulin; the other is a hormone that raises blood sugar, such hormones: adrenaline, glucagon, adrenocortical hormone, Growth hormone and so on.
• Blood glucose levels can be measured with a blood glucose meter. The principle of a blood glucose meter is to measure blood sugar by measuring the amount of current produced by the reaction of glucose in the blood with glucose dehydrogenase in the test paper.
Purpose
• Master the effects of insulin, glucagon, adrenaline, glucocorticoids, thyroxine, and auxin on blood glucose levels by measuring blood glucose levels.
• Learn how to measure blood sugar
Materials and Methods
• Experimental animals: mice
• Equipment and medicines: a set of surgical instruments for mammals, 5 syringes (5ml), 8 boxes with lids, 2% sodium pentobarbital solution, saline, insulin solution, glucagon solution, 1: 10000 adrenaline solution, glucocorticoid injection, thyroxine injection, nuptropin growth hormone injection

Methods and steps
• 1. Random grouping Fourteen healthy mice with similar body weight and similar strains were randomly divided into A and B groups, each group numbered 1, 2, 3, 4, 5, 6, 7,;
• 2. Group A anesthesia treatment: A group of mice were injected with 2% sodium pentobarbital, 0.005ml/g at the end of the mice. After anesthesia, the animals were placed on the operating table and the abdominal cavity was opened on the right side of the xiphoid. , suture the wound;
• In group B, the same incision was made in the area where the mice in group A were operated, and then the wound was sutured. The blood glucose concentration of each mouse was measured (glucometer) and the experimental data was recorded.
• 4. Drug treatment After the mice were quiet, the mice in the two groups were intraperitoneally injected with 0.5 ml of normal saline; the mice in the second group were injected with 0.5 ml of glucagon, and the mice of the third group were injected with 0.5 ml of epinephrine; Mouse No. 4 was intraperitoneally injected with 10 U/10 g of insulin; No. 5 mice were intraperitoneally injected with 0.5 ml of glucocorticoid; No. 6 mice were intraperitoneally injected with thyroxine 0.5 ml; and No. 7 mice were intraperitoneally injected with 0.5 ml of growth hormone. Place the mouse in a covered box, measure the blood glucose once every 5 minutes with a blood glucose meter, and record the experimental data;
Precautions
• The mode of administration of this experiment is intravenous. It should pay attention to the correct gesture of capturing animals and the site of injection. At the same time, pay attention to the dosage of the drug, including the dosing of the drug and the quantification of the syringe. In addition, it is usually necessary after the injection of the drug. The reaction of the mouse was observed in a covered box. The reaction was not only affected by the dose but also related to the surrounding temperature. The higher the temperature, the higher the proportion of the reaction.
Experimental expected result
• The blood glucose concentration of the mice before use as a reference;
• The blood glucose concentration of group A mice was significantly lower than the reference concentration. The blood glucose levels of mice 2, 3, 5, 6, and 7 were significantly higher than the reference concentration, and the blood glucose concentration of mice 1 decreased slightly.
• The blood glucose concentration of group B mice gradually decreased and then returned to the reference concentration. The blood glucose levels of mice 2, 3, 5, 6, and 7 gradually increased and then returned to the reference concentration. The blood glucose concentration of mouse No. 1 did not change significantly.

Effect of recombinant human growth hormone replacement therapy on the incidence of diabetes in children and adolescents

Growth hormone (GH) replacement therapy is the only treatment that has proven to be effective in patients with growth hormone deficiency [1⁃2], and has significant growth-promoting effects after GH replacement therapy. As early as 1958, the case of successful treatment of growth hormone deficiency (GHD) in children with growth hormone was first reported abroad [3]. In the 1980s, “inclusion body technology” made it possible to obtain recombinant human growth hormone (rhGH). DNA recombination technology enabled rhGH to be mass-produced, overcoming the yield limitation of pituitary extracts, and also solved some application safety problems. [4]. RhGH has been used clinically for more than 20 years, and its effectiveness has been affirmed, but safety has received wide attention. On the one hand, GH antagonizes the effect of insulin on glucose metabolism by reducing peripheral blood glucose intake, promoting glycogenolysis and gluconeogenesis; on the other hand, GH can also promote lipid decomposition, thereby promoting lipid oxidation and inhibiting glucose decomposition [5] . Due to the antagonistic effect of growth hormone on insulin and the effect of increasing blood sugar, its influence on the incidence of diabetes has been paid more and more attention. This paper will discuss the effects of growth hormone on glucose metabolism and diabetes incidence in children and adolescents in the existing research, in order to cause Physicians are concerned about changes in glucose metabolism in patients receiving GH replacement therapy.
1. Sources of follow-up data for children and adolescents with growth hormone replacement therapy
It is not easy to evaluate the effect of growth hormone replacement therapy on the incidence of diabetes. First, the incidence of diabetes after growth hormone replacement therapy is relatively low. It has been reported that the unit of measurement is every 100 000 treatment years [6]. To obtain statistical significance, there must be a large sample size and long-term follow-up. Secondly, the onset time of diabetes can be separated from the use of growth hormone for several decades, and it is affected by many factors such as heredity, eating habits and drugs, which brings great difficulty to clinical research. Retrospective studies can count the incidence of early growth hormone replacement therapy in children and adolescents, but inevitably bring in various biases. Although prospective studies can avoid bias as much as possible, the time to follow up patients is relatively short. Finally, the incidence of diabetes itself is susceptible to factors such as genetic background, lifestyle, and age of life. Therefore, to scientifically evaluate the relationship between diabetes mellitus and growth hormone use, it is necessary to find a relatively matched control population.

To objectively evaluate the risk of growth hormone replacement therapy for long-term diabetes, first understand the source of the original follow-up data. At present, there are several database and clinical research projects of rhGH in the world. These databases are generally derived from the safety supervision of pharmaceutical companies after listing. The cumulative number of patients is tens of thousands, and the follow-up time is generally more than 10 years. They are respectively Pfizer. , Eli Lilly, Genentech and Novartis. These databases conduct drug safety studies at regular intervals, including investigations into the incidence of diabetes. (1) Pfizer International Growth Database (KIGS): A patient database established by Famasia Pu Cong Pharmaceutical Co., a company that produces rhGH, which was incorporated into Pfizer in 2003. It is a large international drug epidemiology. The main purpose of the survey was to monitor the safety of growth hormone replacement therapy in children and adolescents. Among them, there were only 23,000 children and adolescents enrolled in the 10 years from 1987 to 1997, and nearly 60% (about 14,000) were children and adolescents with growth hormone deficiency [6⁃7]. (2) International Study of Genetics and Neuroendocrinology in Dwarfs (GeNeSIS): A multi-country follow-up survey funded by Eli Lilly and Company, which was administered to children and adolescents treated with Eli Lilly’s humatrope growth hormone. The survey enrolled more than 11,000 children and adolescents between 1997 and 2007, including about 5 500 children and adolescents in the United States [8]. (3) National Growth Collaborative Study (NCGS): A long-term prospective follow-up from 1985 to 2010, followed by patients who underwent growth hormone in Genentech under the age of 17 in North America (USA and Canada). Since 2006, the study has been conducted in France, Germany, Italy, Romania, and the United Kingdom, and has been renamed International Growth Research (iNCGS), which targets 3,000 subjects under 18 years of age [9].
(4) PATR Children Study (PATRO): A multi-country, multi-center follow-up survey of adverse drug events in children and adolescents using omnitrope (a rhGH) in 10 European countries [10].
2. Analysis of the impact of GH application on the incidence of diabetes
Looking at the follow-up study of rhGH for nearly 20 years, it can be found that not only the conclusions of the research between different databases will be different, but also the data analyzed in a database with different time periods will be inconsistent [6⁃10]. This indicates that the objective and accurate analysis of the impact of rhGH on the risk of long-term diabetes can not be concluded only by a short-term, single-database study, which requires a long period of follow-up to accumulate enough data samples, and needs to integrate various databases. The research report looks at it.
1. GH application has no effect on the incidence of diabetes: 1991
Czernichow et al [11] analyzed follow-up records of 8 100 children and adolescents receiving growth hormone replacement therapy in the KIGS database and found that only one child and adolescent had type 1 diabetes (T1DM) after using growth hormone, and two patients developed type 2 diabetes (T1DM). Diabetes (T2DM), and one of them has high risk factors such as obesity and family genetic predisposition. The short follow-up of this study inevitably ignored some of the children and adolescents who had not developed diabetes at the time.
In 2000, Maneatis et al [12] analyzed more than 33,000 patients in the NCGS database from 1985 to 1999 and found that there was no increase in the risk of diabetes compared with the normal control population. As of September 2012, PATRO initial results analysis found
In 184 research centers in 10 European countries, 1 837 patients with growth hormone omnitrope were treated with no confirmed diabetes in 10 children [10]. In 2013, Shigeru et al [13] analyzed 1 129 GHD and 90 patients with Turner syndrome in the (GeNeSIS) database using riptropin GH for 4 years, and the GH dose was 0.175 and 0.35 mg·kg in GHD patients and TS patients, respectively. 1·Week-1, the effect on glucose metabolism was found to be very low. In the GHD group, 7 patients had impaired glucose tolerance, only 2 patients developed T2DM related to GH therapy, and only 1 patient in the TS group developed T2DM. Not related to GH applications. Ricardo et al [14] found that T⁃ cells mediate autoimmune disease in a T1DM mouse model, GH overexpression can regulate immune response, reverse the progression of diabetes, the mechanism may be GH acting on β cell proliferation and apoptosis, by triggering environmental cells The factor promotes polarization of anti-inflammatory macrophages, maintains T cell activity, and inhibits Th17 cell plasticity.
2. GH application increases the incidence of diabetes: In 2000, Cutfield et al [6] retrospectively analyzed the KIGS database, followed up the participants between 1987 and 1997, and collected data related to glucose metabolism such as family history, hematology Diabetes risk factors (obesity, Turner syndrome, Pradaer⁃ Willi syndrome, etc.) and related drug use, each patient received growth hormone therapy for more than 3 months. The “expectation rate” of type 1 and type 2 diabetes in the KIGS group was calculated by demographic data by matching the national distribution of KIGS. The study found that the incidence of T1DM in children treated with growth hormone replacement therapy did not increase compared to the “expectation rate”; the incidence of T2DM was 33.4 per 100 000 treatment years, which was six times higher than the “expectation rate”. About 80% of adolescents with T2DM are obese at the time of diagnosis, while those with obesity are very rare in patients with T2DM after receiving growth hormone therapy, so the increase in the incidence of T2DM in patients receiving growth hormone therapy is not significantly affected by obesity. It is worth noting that in those patients with T2DM, diabetes is not relieved by stopping the use of growth hormone, indicating that the symptoms of T2DM are not caused by the transient effects of growth hormone. The authors believe that this may be related to the growth of hormones in patients who have not received growth hormone therapy.
In 2010, Bell et al [15] re-examined the NCGS database, 55 000 patients received growth hormone replacement therapy in 1985 and 2006, and found 33 patients with T1DM, the incidence was not significantly higher than the general population. Twenty patients had T2DM (including 2 patients with Papill’s syndrome) during or after the use of growth hormone, with an incidence of 14 per 100,000 treatment years. Although it is lower than Cutfield’s research, and due to the difference in objective conditions, the patient’s weight, lifestyle and other data could not be systematically counted. This incidence is still significantly higher than the T2DM rate in children in the United States. Personally, these two data are relatively poorly comparable. Maneatis’s research target is mainly NCGS database. Most of the patients are enrolled in the US and Canada. The Cutfield study is mainly based on the KIGS database. The patients enrolled are more geographically rich in glucose metabolism. There is a difference in the expected value of the abnormality.
In 2011, Child et al [8] analyzed more than 11,000 children and adolescents using growth hormone replacement therapy in the GeNeSIS database, compared with the average children in the US SEARCH for Diabetes in Youth Study database and found median treatment of average growth hormone. With a life of 1.8 years, the incidence of T1DM did not increase, and the incidence of T2DM was 6.5 per thousand, much higher than the average, further supporting the above conclusions.
Although the above studies do not support the use of growth hormone therapy to aggravate the risk of T1DM, a controlled study by Bonfig et al [16] found that exogenous growth hormone may aggravate the symptoms of T1DM hyperglycemia, affecting age, gender, duration of diabetes, ethnicity, etc. After matching the factors, children and adolescents with GHD and T1DM need to use a larger dose of insulin (1 U·kg⁃1·d⁃1) to control blood glucose, while children and adolescents with T1DM only need 0.75 units·kg⁃1 · insulin dose of d⁃1.
Third, the effect of growth hormone replacement therapy on the incidence of diabetes
Growth hormone antagonizes the regulation of insulin on blood glucose under physiological conditions, and has the effect of raising blood sugar. Therefore, neonates with growth hormone deficiency often have clinical symptoms such as hypoglycemia [17]. The incidence of diabetes in patients with acromegaly with excessive growth hormone secretion is significantly increased, reaching 20% ​​ 50%, confirming that growth hormone can increase insulin resistance and affect glucose metabolism [18]. A lot of research suggests that
The glycemic effect of GH may mainly produce insulin resistance by inhibiting the oxidation of glucose by peripheral tissues and the non-oxidative pathway of glucose in the body, increasing insulin release and FFA excretion. Because diabetes is affected by factors such as age, race, eating habits, environment, family history, body mass index, etc., different doses, monitoring methods, treatment time, etc. will affect the results of glucose metabolism, and the conclusions of GH on blood glucose are inconsistent. Studies have also found that GH has an insulin-like effect, and short-term application can lower blood sugar and inhibit fat degradation [19]. Long-term GH treatment may improve lipid metabolism, decreased fat mass, and may even improve glucose metabolism and insulin sensitivity [20⁃21].
Based on the above research report, we can see some common conclusions: (1) There is no evidence to support the risk of T1DM and because of the increase in growth hormone replacement therapy, but growth hormone deficiency in children and adolescents with T1DM requires greater doses of insulin control. Blood glucose; (2) The current research supports the incidence of T2DM after treatment with growth hormone, and the occurrence of diabetes does not disappear with the withdrawal of growth hormone, suggesting that this effect may occur in advance with growth hormone-promoting diabetes-susceptible population Diabetes-related, because the occurrence of T2DM often takes a relatively long time to show significant differences, so objective assessment requires longer follow-up. It is worth noting that the above studies also have certain limitations. First, because the incidence of diabetes has increased year by year in the past two or three decades, and the incidence of different physiological and social backgrounds is different, it is difficult to estimate the incidence of diabetes in the general population. Second, since most studies are retrospective, there is inevitably bias, and the effectiveness and safety of GH need to be studied through large-scale, long-term, prospective, randomized, double-blind aspects, but this requires a lot of financial support. Finally, all cohort subjects were not included in the Asian population on a large scale. Whether the above conclusions are applicable to children and adolescents in China is subject to scientific research and clinical practice testing.
Fourth, summary
The impact of growth hormone replacement therapy on glucose metabolism in children is currently lacking in uniform conclusions, and further large-scale long-term experiments are needed to explore the safety of treatment. By analyzing the database of large-scale epidemiological surveys, the incidence of various types of diabetes in children with growth hormone replacement therapy is calculated, and the risk of diabetes in children is more concerned, which provides a reference for clinically focused patients. Summarizing existing research data, GH application may increase the risk of diabetes incidence, and weigh the pros and cons before applying GH replacement therapy. Before using growth hormone therapy, we need to routinely evaluate patients’ blood glucose levels, including glycated hemoglobin, fasting blood glucose and insulin concentration. For children with high risk factors for diabetes such as obesity, Turner syndrome, intrauterine growth retardation, and Papillon’s syndrome, children and adolescents need to pay attention to follow-up changes in blood glucose.

Standardized application and safety monitoring of recombinant human growth hormone in pediatric clinical

In 1956, pituitary derived human growth hormone (phGH) was isolated from human pituitary and subsequently applied to the treatment of growth hormone deficiency (GHD). Since the beginning of 1984, dozens of Creutzfeldt-Jakob lesions have been reported in patients with phGH. In early 1985, phGH was banned by the US Food and Drug Administration (FDA). In the following months, biochemically synthesized growth hormone was approved by the US FDA, but it was quickly discontinued due to its high antigenicity and easy production of antibodies. In the same year, the in vitro synthesis of recombinant human growth hormone (rhGH) was successfully marketed, making it possible for a large number of clinical applications of GH. The US FDA approved its use for the treatment of children with GHD and subsequently approved for chronic renal insufficiency. Pre-transplantation, Turner syndrome, Prader-Willi syndrome, small for gestational age (SGA), idiopathic short stature (ISS), short bowel syndrome, SHOX gene deletion, Noonan synthesis Treatment of short stature in patients with non-growth hormone deficiency |

In the past 30 years, rhGH has become more and more widely used in clinical practice, and its role in promoting growth and improving lifelong high has been recognized. At the same time, the safety of rhGH treatment is also closely watched. European Pediatric Endocrinology Society (ESPE), Lawson, USA. Lawson Wilkins Pediatric Endocrine Society, International Pediatric Endocrinology Society (ISPE), Growth Hormone Research Society (GHRS), American Society of Clinical Endocrinology (AACE), etc. developed GHD and non-growth hormone deficiency short stature children rhGH diagnosis and treatment Guides and consensus are the same. 7 J. The Endocrine Genetic Metabolism Group of the Pediatrics Branch of the Chinese Medical Association also proposed the “Recommendation for the Clinical Application of Recombinant Human Growth Hormone” in 1998. In 2008, the “Guidelines for the Diagnosis and Treatment of Short Stature Children” was formulated to standardize the clinical application of rhGH. Diagnosis and treatment of short stature children [8-9]. However, the clinical application of rhGH still has many problems such as random expansion of application range, irregular diagnosis of diseases, excessive or irregular treatment, and inadvertent monitoring during treatment, which brings uncertain clinical effects and serious safety hazards to rhGH treatment. In 2013, the Endocrine Genetic Metabolism Group of the Chinese Medical Association Pediatrics Branch and the Editorial Board of the Chinese Journal of Pediatrics reorganized and revised the “Recommendations for the Application of Genetic Recombinant Human Growth Hormone Pediatric Clinical Specifications” (“Recommendation”) 010], and in this journal. Out, in order to further guide the norm application of rhGH.

1. Strictly grasp the indications for the clinical application of rhGH

Although rhGH brings good news to patients with short stature, not all patients with short stature need or are suitable for rhGH treatment. Strict control of rhGH indications is a prerequisite for normative application, and clear disease diagnosis is a prerequisite for strict control of rhGH clinical application indications. In the diagnosis of short stature, the patient’s medical history, family history, clinical manifestations, physical examination and related laboratory and imaging results must be analyzed and evaluated. Pay special attention to the following problems in the clinical diagnosis process.

1. Correct evaluation of GH challenge test: GH challenge test is an important basis for the diagnosis of GHD, but the test still has some limitations in clinical application. ‘1’”1: (1) GH challenge test reflects insulin, levodopa The secretion of GH after stimulation with drugs such as clonidine is not the secretion of GH under physiological conditions. Some GH challenge tests suggest that the natural secretion of GH in “normal” children may be lower than that in normal children. (2) Many factors affecting GH challenge test The drugs used in the challenge test, the test methods of GH, and the sexual development status of the children can affect the results of the GH challenge test. Different drug excitations, peak time and peak size are different; different laboratories use different Detection methods and reagents have different diagnostic thresholds. A part of pre-pubertal children with slow growth have been confirmed by GH challenge test to be lower than normal, but re-testing in puberty may rule out the diagnosis of GHD. Therefore, some foreign scholars have suggested that puberty Pre-children should have sex hormone pre-excitation before the GH challenge test, but there is no consensus on this. (3) GH challenge test Off threshold is set manually, Different countries and regions use different diagnostic thresholds.
At present, the international consensus and the standards adopted in China are peak <10 ̈g/L, and some countries adopt more stringent standards such as <7 ̈∥L or 5 anal g/L. (4) The GH excitation test was not reproducible. GH challenge tests were performed with different stimulating drugs, before and after rhGH treatment, and before and after puberty. The results were all different. According to the results of the GH challenge test, GHD misdiagnosis and missed diagnosis may occur. Although the GH challenge test has certain limitations, it still plays a very important role in the diagnosis and differential diagnosis of short stature diseases. Some people think that the peak of GH stimulation test <10 shirt g / L can diagnose GHD, the peak of GH challenge test > 10 bucket g / L can diagnose ISS, both are FDA-approved rhGH indications, therefore, no need to carry out GH In the provocation test, patients with short stature can start using rhGH therapy. This view is very wrong. First, it ignores the diagnostic significance of the GH challenge test. The GH challenge test is not only an important basis for the diagnosis of GHD, but also the diagnosis of GH receptor deficiency and growth hormone neurosecretory dysfunction in combination with IGF1, IGF! production test, and GH natural secretion measurement. Second, this view confuses the definition of ISS and non-growth hormone deficiency short stature. Non-growth hormone deficiency includes not only ISS, but also short stature caused by a lack of growth hormone deficiency, such as Turner syndrome, Prader. Willi syndrome, SHOX gene deletion, Noonan syndrome, etc. In addition, under the premise of unclear diagnosis, humatrope rhGH treatment is started only because of short stature, it is difficult to determine the correct treatment plan, and the safety of treatment cannot be guaranteed.
2. Defining the diagnosis of children with ISS: The diagnosis of ISS is still controversial. ISS is essentially a group of diseases that are currently short-lived due to unclear causes. Compared with normal children, children with ISS had a peak GH of >10 ̈g/L, but the basal GH level, GH peak, and total GH secretion were lower than normal children (a 0.48 SDS, a 0.36 SDS). , a 0.76 SDS); 25% of children with IGF1 decreased or were at a normal low limit, and some patients had normal or elevated IGF1 levels, but there was IGF1 resistance. 1 cited. With the in-depth study of hypothalamic-GH-IGF1 axis function and genetics, more and more evidence indicates that the hypothalamus may exist in children with current diagnosis of ISS. GH. Abnormality of IGFl axis function. Although the results of GH challenge test showed normal, the natural secretion of growth hormone was not detected 24 hours or 12 hours, but the natural secretion of GH could not be found to decrease. The abnormal function of GH promoter affected GH naturally. Secretion does not affect the peak of GH challenge test; abnormal GH molecules lead to GH deficiency biological activity; related gene defects in GH signal transduction pathway lead to decreased responsiveness to GH, such as GHR, STATSb, ALS, IGF1, IGFlR gene abnormalities, etc. 3. 14 o. With the widespread clinical application of genetic analysis technology, more GH may be found in children with ISS. IGFl axis-related genes or signaling molecules are abnormal, thereby separating the disease with a clear cause from the ISS.
3. Correct evaluation of the role of predicting adult height: The US FDA defines normal height as 160.0 ca for men and 149.9 cm for women. At present, there is a lack of scientific, effective and suitable method for predicting height evaluation of children with short stature in China. The commonly used Bayley-Pinneau (B-P) method is based on observations of healthy children in the UK in the 1950s and is not suitable for the height prediction of Chinese short stature children. And the study found that the degree of bone age lag can affect the accuracy of predicting height. The average adult height of children with a bone age of about 2 years is close to the predicted height of the adult. The height of the adult with a bone age of more than 2 years is far lower than the predicted height of the adult. The height of the adult without the bone age is much higher than the original predicted height of the adult 1151. . Predicting the inaccuracy of height makes it impossible to be the indicator ‘3’ for starting rhGH treatment. 5 J, the clinical should not simply decide whether to start rhGH treatment based on the predicted height.
4. To clarify the clinical scope of rhGH treatment: in addition to the FDA-recommended rhGH indications, clinical data showing clinical signs of central precocious puberty, congenital adrenal hyperplasia, congenital hypothyroidism, etc. After treatment, rhGH treatment can improve the growth after the growth and backwardness is predicted, and the prediction of adult height is obviously damaged. However, more evidence-based medicine is needed, which is not used as a routine clinical application. Because of the current lack of scientific psychological assessment methods, rhGH is not used for the purpose of improving the psychological behavior of children with short stature.
In addition, height is affected by many factors such as heredity, endocrine, nutrition, disease, etc., and there are obvious ethnic and individual differences. rhGH should not be used for the treatment of normal short children for the purpose of improving their height. In the course of work or life, society should also avoid discrimination or misleading of height. Second, adhere to rhGH standardized treatment standardized treatment is to obtain better efficacy and reduce the adverse reactions. Children with short stature should adhere to standardized treatment once they are clearly diagnosed with indications for rhGH treatment. This “recommendation” describes the rhGH treatment plan for different diseases.

1. Time to start medication: In addition to GHD, the initial treatment time for other indications varies with age and growth and development indicators. The age of ISS initial treatment was 5 years old; the height of children with SGA I>4 years old was still lower than the average height of children of the same age and normal sex, and the treatment was considered; the height of Turner syndrome was 5th in the growth curve of normal female children. When the percentile is below, the treatment of rhGH should be started, and treatment can be started even at 2 years of age; the age of initiation of PWS is not yet uniform, but it is generally believed that it is beneficial to start rhGh before obesity (usually around 2 years old). .
2. Therapeutic dose: Within a certain range, there is a dose-dependent effect of rhGH treatment, but the therapeutic dose is not as large as possible. Studies have shown that ̈⋯, low-dose long-term treatment can achieve better life-long. The therapeutic dose is related to the disease type, puberty status and the like. The initial therapeutic doses for different diseases vary, with lower doses for GHD patients and slightly greater doses for Turner syndrome, SGA, and ISS. The pre-pubertal treatment dose is slightly smaller, while the puberty development dose is slightly larger. However, the maximum amount should not exceed 0.2 U / (kg · d), long-term super-physiological dose of rhGH application still requires larger sample, long-term safety monitoring data.
3. Treatment course: rhGH treatment varies depending on the condition. The height SDS continues to improve with the treatment time. In order to improve adult height, rhGH treatment should last at least 1 year. In the short-term, especially within half a year, rhGH treatment is difficult to achieve the goal of improving lifelong high, and it is not recommended in clinical practice.
4. Time to stop the drug: height after treatment is greater than normal body height by 2 standard deviation; or close to adult height, that is, growth rate <2 cm / year, boy bone age > 16 years old, girl bone age > 14 years may consider discontinuation. However, children and parents’ satisfaction, economic reasons, etc. are often common factors affecting withdrawal. In order to improve body composition, lipid metabolism, cardiac function, etc., patients with GHD and PWS can be used in adulthood, but the therapeutic dose is smaller ̈’22|.
5. Efficacy assessment: dose adjustment should be made according to the patient’s treatment effect, body weight change, puberty status and IGF1 level during the treatment process, and pay attention to the efficacy evaluation. In patients with good compliance, and if the treatment dose is appropriate, if the growth rate is not increased, serum IGFI levels are not increased, usually suggesting that the treatment is ineffective, and further evaluation of the diagnosis is necessary. After 2 years of initial treatment, if serum IGF1 levels are above the normal range, especially above 2.5 SDS, reduction or discontinuation should be considered. The overall treatment of rhGH should follow the principle of individualization, using early treatment, full dose, and long course of treatment. In the rhGH treatment evaluation process, the rational allocation of medical resources should also be fully considered, especially the input-to-benefit ratio, benefit and risk assessment. Clinicians should not simply decide the treatment and treatment by the satisfaction of society, parents and patients on height. .
Third, pay attention to the safety monitoring of rhGH treatment Some clinicians pay more attention to the effectiveness of rhGH treatment, pay attention to the monitoring of growth and development indicators, neglect safety monitoring, and safety is one of the key points of standardized treatment.

1. Familiar with the possible adverse reactions during rhGH treatment: The related adverse reactions of rhGH treatment are currently reported. 2}29 o have benign intracranial hypertension, effects of glucose metabolism, hypothyroidism, femoral head slippage, scoliosis, possibility of inducing tumors, pigmented nevus, adenoid hypertrophy, enlarged hands and feet. Local redness and rash are not common, and otitis media, pancreatitis, and male breast development are also reported. Long-term treatment with rhGH can reduce insulin sensitivity and increase insulin resistance. Some patients have impaired glucose tolerance, but most of them are temporarily reversible, and rarely develop into diabetes ‘23.26I. In the first few months of rhGH treatment and even after 1 year of treatment, some children may have hypothyroidism. 2孓26I. Skeletal changes such as femoral head slip, scoliosis, and large hands and feet are caused by excessive growth, rather than direct adverse reactions of rhGH. It has been reported that rhGH has potential carcinogenicity and can promote tumor growth, but there is no clinical evidence that rhGH treatment increases tumor neoplasia, recurrence or secondary tumor development. In rhGH-treated patients, the incidence of new, recurrent, and secondary tumors was higher in organic growth hormone deficiency (OGHD), followed by chronic renal insufficiency and Turner syndrome. There is data showing that patients with first-stage tumors are leukemia and central nervous system tumors, and rhGH patients have an increased risk of secondary tumors [23.26I. Although rhGH may increase the number and size of pigmented nevi, there is no evidence to increase the risk of melanoma [27]. The current study also does not confirm that there is a causal relationship between childhood rhGH therapy and increased mortality after adulthood, but it requires close attention.

2. Strict screening before treatment and close monitoring during treatment: Although the incidence of total adverse reactions in rhGH treatment is less than 3%, in order to avoid the above-mentioned possible adverse reactions, thyroid function should be routinely checked before rhGH treatment (if there is hypothyroidism, it is necessary to adjust thyroid function to normal, and then start rhGH treatment); fasting blood glucose, insulin, glucose tolerance, glycosylated hemoglobin detection if necessary; routine pituitary MRI detection. rhGH is contraindicated in the following cases: active tumors, active psychosis, severe obesity, uncontrolled diabetes, uncontrolled severe obstructive sleep apnea, etc. Bloom syndrome, Fanconi syndrome, Down syndrome, etc. are also associated with rhGH treatment because of the risk of tumorigenesis. Have a family history of cancer or have the following diseases: central nervous system tumors, leukemia; histiocytosis; craniopharyngioma; mixed gonadal dysplasia, familial adenomatous polyposis, neurofibromatosis, etc. with caution for rhGH treatment. 2}26 o. For severe obesity, uncontrollable weight gain, gastroesophageal reflux, poor respiratory protection, respiratory problems, especially in children with obstruction of air, should also be treated with rhGH with caution. The population should weigh the pros and cons according to the condition, and decide whether to carry out rhGH treatment under the premise of full informed consent. The vast majority of tumor recurrence occurred within the first 2 years, so patients with intracranial tumors are not recommended to undergo rhGH treatment within 2 years after radiotherapy.

In the course of rhGH treatment, in addition to the measurement of growth and development indicators, biochemical indicators should be routinely monitored: thyroid function, fasting blood glucose and insulin, IGF1 and IGFBP3 levels were monitored every 3 to 6 months. Liver and kidney function, adrenal function, glycosylated hemoglobin, and bone age are monitored annually. Pituitary magnetic resonance was reviewed in some children with organic growth hormone deficiency if necessary. At each follow-up, attention should be paid to the presence of adverse reactions.

3. Strengthening long-term follow-up of rhGH therapy and domestic database construction: In order to better monitor the safety and effectiveness of long-term rhGH treatment, the National Cooperative Growth Study (NCGS) and the Pfizer International Growth Database (the Pfizer International) have been established abroad. Growth Database, KIGS), Australia and New Zealand Growth Database (Ozgrow) and other III’26’30J, large sample and long-term data from the database provide a basis for further standardization of rhGH treatment. The Endocrine Genetics Group of the Chinese Medical Association’s Pediatrics Branch led the establishment of the Chinese rhGH treatment short patient database in 2009. The construction of the database is constantly expanding and improving, and it is expected to provide data support for the standardized treatment of Chinese short patients. Although the effectiveness and safety of rhGH therapy have been widely verified, its clinical application has strong professionalism. Prescription physicians are required to have a strong endocrine basis and clinical knowledge, and are deeply aware of the importance of strict indications, standardized treatment and monitoring for the health of children. For such highly specialized drugs, medical management institutions should strengthen the hierarchical management and gradually implement the sub-professional access system to ensure the scientific, rational, effective and safe application of drugs.