The clinical application of rhGH: Growth hormone (GH) is a protein hormone produced by the anterior pituitary growth hormone cells. GH is necessary for normal growth and plays an important role in the function of the heart, kidneys, skin, internal organs, bones, muscles, gonads, etc., in addition to increasing height, and has a major impact on the metabolism of sugar, fat and protein. Although growth hormone deficiency is not as life-threatening as diabetes caused by insulin deficiency, it can cause a series of abnormal manifestations such as dwarfism, osteoporosis, muscle dysplasia, susceptibility to cardiovascular diseases, sexual dysplasia, and easy aging, etc. In 1958, GH extracted from the pituitary gland of a recently deceased person was used to treat patients with growth hormone deficiency (GHD). Although the efficacy was remarkable, it was not easy to obtain, the yield was very small, and the cause of death was different in different people, and there was a risk of infection with serious infectious diseases, which could not meet the needs of patient treatment. It was not until 1985 that human growth hormone (rhGH), made by recombinant gene technology, was officially marketed and better applied in clinical practice. Recombinant human growth hormone (rhGH) has been widely used in the treatment of pituitary GHD with better efficacy and experience. With the continuous research on the causes of short stature, the application of rhGH has been extended to the treatment of non-GHD short stature, such as congenital ovarian hypoplasia (Turner syndrome), small for gestational age children, Prader-Willi syndrome, chronic renal failure and adjuvant therapy for precocious puberty. The U.S. Food and Drug Administration (FDA), the world’s most stringent drug review agency, approved growth hormone indications: 1985 Growth hormone deficiency (GHD) in children 1993 Chronic renal insufficiency before kidney transplant 1996 HIV infection-related failure syndrome 1996 Turner syndrome short stature 1997 GHD replacement therapy in adults 2000 Prader-Willi syndrome 2001 Smaller than gestational age (SGA) 2003 Idiopathic short stature (ISS) 2003 Short bowel syndrome 2006 SHOX gene deficiency in children without GHD In recent years, rhGH has also been found to have outstanding efficacy in anti-aging and weight loss treatment, and a Dutch study A Dutch study suggests that rhGH has a beneficial effect on mental development. Since GH is a protein with a molecular weight of about 22 KD, if taken orally, it will be broken down. After decomposition, it is no longer GH, and even if it is taken orally without being decomposed by certain methods, the large molecules cannot be absorbed through the gastrointestinal tract. Similar to the insulin used by diabetics, it is a human dream to make an oral preparation, but it is difficult to realize in the near future. At present, rhGH is used in a similar way to insulin, and the lyophilized powder is dissolved in the injection water distributed by the manufacturer and then injected by insulin needle (BD needle), once a night about one hour before bedtime. Water can also be injected by general BD needle, or possibly by “Novo Pen”. Because the BD needle is very fine, than the acupuncture needles used in Chinese medicine is also fine, fine to a certain degree of pain is not obvious. Has anyone seen the pain of acupuncture? Normal people usually have very little GH in the blood, only at night during deep sleep will appear several peaks, to determine whether GH deficiency, only check the usual value can not reflect the level of GH, must be through drug stimulation test (stimulation test), and constantly a small amount of blood collection (usually commonly used intravenous needle, can reduce the pain of multiple venipuncture), in order to measure the peak secretion of growth hormone. The peak value is the criterion to determine whether GH is deficient or not. The peak value of GH is very low, but the peak value can be more than 50 times the usual value, and the half-life (the time required for the concentration in the blood to drop by half) is very short, usually only about 20 minutes, therefore, GH deficiency will not cause too much GH or affect its own GH secretion after the application of therapeutic doses. The average peak value in mid-puberty is 22.4ng/ml, which is more than twice the adult value. In the middle of puberty, the total amount of GH secreted in a day can reach 60ug/kg/day, which is more than three times of the adult value. The normal treatment amount, and the total daily secretion of normal people still in a certain gap, but in the appropriate time application, and its own secretion peak overlap, it can reach a more normal secretion peak, play an effective improvement of lifelong high role and normal metabolism required for GH peak. In 2003, the FDA approved the use of rhGH for the treatment of non-GH deficient idiopathic short stature (ISS). Since it is officially approved for use in non-GH deficient individuals, it must have at least a good safety and efficacy profile, one or the other being essential. The etiology of ISS is not clear and may be due to a combination of underlying factors. There may be insufficient or disturbed total GH secretion and poor GH activity; there may be GH receptor abnormalities, mutations or receptor insensitivity; there may be a relative deficiency of insulin-like growth factor-1 (IGF-1), etc. With the improvement of biochemical and genetic testing techniques, the etiology of ISS may be gradually found in the future. Other indications: ① chronic renal failure; ② hepatic failure; ③ dilated cardiomyopathy; ④ surgical field: burns, severe trauma, post-surgery, total intravenous nutrition, etc.; ⑤ improving immune function; ⑥ other: anti-aging, certain infertility. Dosage and course of treatment: The dosage and course of treatment vary depending on the type of disease, age and bone age at the time of treatment. Compared with foreign countries, the overall situation in China is that the dosage is low and the course of treatment is short. Recommended reference dosage: GHD: 0.1-0.12u/kg/d for preschool and school-age children, with appropriate dosage increase from adolescence to 0.15u/kg/d or greater. For other diseases such as ISS, SGA, TS, etc., the starting dosage is about 0.15u/kg/d, and 0.2u/kg/d or even greater in adolescence. The duration of treatment varies depending on the disease, and factors such as the degree of height deficiency and the wishes of the child and parents should be considered. The use of rhGH in children with precocious puberty Precocious puberty affects the final height, and the earlier the onset, the greater the impact, especially in rapidly progressing precocious puberty. GnRH-a is currently used in combination with rhGH in about 2/3 of patients with precocious puberty abroad. Regarding the use of high-dose rhGH in patients with pubertal dwarfism: In 2003, the US FDA approved a high dose of 0.3 u/kg/d for the treatment of patients with pubertal dwarfism. However, the current dose used in China is generally relatively small and the effect is good. The current common dose in China is: 0.15~0.2 units/KG/day. The theoretical basis of high dose in adolescence: 1. the age change of GH secretion; 2. the growth of height in adolescence has a great influence on the final height; 3. the decrease of muscle sensitivity to rhGH after the application of GnRH-a. Diseases in which GH should be contraindicated or used with caution: active tumor, diabetes mellitus with severe complications, Down syndrome, Bloom syndrome, megaloblastic anemia, etc. A history of tumor or diabetes in the family is not a contraindication to growth hormone use. The world’s leading pediatric endocrine societies have reached a consensus in Mexico in 2007 that growth hormone does not induce tumors. Analysis of the efficacy of rhGH: The clinical efficacy of rhGH is most significant in those with GH deficiency. In the absence of other diseases, those with small bone age before puberty can generally grow 8 to 14 CM per year, and very rarely even reach about 20 CM/year, which can generally effectively improve lifetime height by 5 to 7 CM/year. As the bone age increases, the growth rate and the amplitude of improving lifetime height will gradually decrease after applying rhGH, generally in the first year after menarche, the annual growth rate of girls will only be about 6-9CM, and the annual improvement of lifetime height will be 3-4CM. More than two years after menarche, the bone age is basically closed, it is impossible to have treatment opportunities. After boys become vocal, their own growth rate begins to decline, and the treatment effect becomes gradually worse as in girls after menarche. Discontinuation indicators are the same as for girls. Growth hormone deficiency (GHD) is also divided into complete (normative peak GH of excitation test is less than 5ng/ml) and partial (peak GH of excitation test is between 5 and 10mg/ml), and relatively speaking, the treatment effect of complete GHD is better than partial. In GHD, because the cause is difficult to resolve, theoretically, medication should be used for life. However, since the harm of GHD is often not immediate and obvious, at present, both domestically and abroad, including countries where it is applied free of charge in childhood, the drug is currently only discontinued after a more normal height is achieved through treatment. In adulthood, it is appropriate to use it in case of larger surgeries or more serious burns, etc., where the lack of GH makes wound healing more difficult. There is no obvious course of rhGH treatment, and the duration of application depends mainly on the difference between the height at the time of treatment and the normal height of the same age, the larger the difference, the longer the total treatment time. The earlier the application of GH, the better it is (excluding children under 2 weeks of age here, because children’s growth is regulated differently in different growth periods, within 1 week of age, the intrauterine growth is regulated by metabolic axis, after 1 week of age, it is gradually changed to GH axis regulation, after 2 weeks of age, GH regulation is the main focus), and the early improvement of dwarfism symptoms is beneficial to reduce the low self-esteem and low self-esteem caused by dwarfism. The early improvement of the symptoms of dwarfism will help to reduce the low self-esteem and retreat psychology caused by dwarfism, which is more conducive to the normal growth of children. However, it is not necessary to stop using it when the growth rate is too low, as in the case of those with older bone age. It can be applied for two to three years, when the height reaches the normal height of the same age or slightly higher, stop using. It can be discontinued when the height reaches normal or slightly higher for the same age, and then continued when the height is significantly lower again. For idiopathic dwarfism (ISS, including some familial dwarfism), since GH is not deficient, the cause of dwarfism is often due to GH secretion disorder or other abnormalities in the GH axis (such as low IGF conversion or activity or low sensitivity of GH and IGF receptors). The effect is generally slightly worse than in GHD patients. In prepubertal children, the annual growth rate after application is generally only about 7-12 CM, and the annual increase in lifetime height is generally 3-5 CM. Since Turner syndrome (TS) is a congenital disorder caused by the absence of an X chromosome, untreated lifelong height will often be less than 140 CM. Since chromosomal abnormalities cannot be changed, the primary treatment is to improve height. Although TS patients are often associated with GH deficiency, the results are generally slightly worse than those of ISS patients, and there are complete and chimeric forms of TS, with chimeric forms having slightly better results than complete forms and, in a few cases, even better results than ISS patients. SGA is mainly due to intrauterine growth retardation, resulting in low length and weight at birth. rhGH treatment for SGA has similar efficacy to ISS. For those with chondrodysplasia, rhGH is also commonly used for treatment because the lifetime height will be too low and there is a lack of effective treatment. However, the treatment effect is poor and the efficacy is not reliable. For Russell-Silver syndrome, Cushing syndrome, diabetic dwarfism, phenylketonuria (PKU), mucopolysaccharide deposition, congenital adrenocortical hyperplasia, etc. rhGH treatment is also currently recommended, but the efficacy varies, with a few treatments having fair results and most having poor results. for Laron syndrome (complete GH receptor insensitivity) and osteogenesis imperfecta, etc. Laron syndrome accounts for about 0.5% of patients with dwarfism and is often associated with GH deficiency, and because of the difficulty of detection, it is not possible to exclude the possibility of a daily diagnosis of GHD combined with complete GH receptor insensitivity. Other diseases too! Does growth hormone promote bone age growth? It is often said that growth hormone promotes bone growth, but this is clearly a misconception, and in 2007, leading experts from the major global pediatric endocrine societies in the United States, Europe, and Asia Pacific reached a consensus at a meeting in Mexico that normal doses of growth hormone do not promote bone growth or sexual development. The reason why some people have this opinion is mainly caused by one-sided understanding. Growth hormone is more often used in children with growth hormone deficiency, such children, bone age is often low, after the application of growth hormone to make growth hormone basically normal, the backward bone age has a tendency to approach normal bone age, easy to be mistaken as promoting bone age growth, there are many children who apply growth hormone, has entered puberty, the rapid growth of bone age in puberty is also easy to be mistaken as being caused by growth hormone. Because of the medication period, it is easy to consider any problems that arise toward the effects of the drug. There is sufficient evidence that the use of aromatase inhibitors in boys (because they are not suitable for girls and are prone to boyhood) prevents the conversion of androgens to estrogens and results in almost no growth in bone age (because they have not yet been officially approved, they are not yet used clinically, but only for research), but the amount of aromatase inhibitors does not inhibit the secretion of gonadotropin-releasing hormone (GnRHa) as much as it does growth hormone secretion, and inhibition of growth hormone receptor sensitivity. This suggests that bone age growth is primarily related to estrogen (which is also present in boys). Besides, growth hormone is often combined with gonadotropin-releasing hormone (GnRHa) to treat true precocious puberty, and if it would significantly promote bone growth, it would not be used for precocious puberty. There is also gigantism, that is, patients with increased secretion of growth hormone, generally do not have precocious maturity or early closure of bone age phenomenon, if growth hormone promotes bone age growth, patients with gigantism will not become giants. And if growth hormone will obviously promote bone age growth, it can not be used to improve the lifetime height, the FDA will approve its use to improve the lifetime height? Would so many people still be spending so much money on long-term use? Possible reasons for poor efficacy in patients treated with rhGH are: i. Need to re-evaluate the diagnosis: e.g. disease that is not sensitive to growth hormone, disease that requires a larger dose and the dosage is small, etc. ii. poor compliance with treatment. The influence of other coexisting diseases. IV. Potential hypothyroidism. V. Influence of other drugs used at the same time, such as adrenocorticosteroids, sex hormones, etc. VI. Problems with injection technique. VII. Epiphysis has closed. VIII. Other: such as psychological factors, excessive stress, diet and exercise have some influence. IX. Drug quality, transport or storage process of drug efficacy impairment X. Possible GH or IGF receptor insensitivity or Laron syndrome. If the growth rate decreases significantly after 3-6 months of drug use, in addition to considering whether the bone age is too large, whether the weight increases significantly and other reasons need to adjust the dose, a more reliable basis is to recheck IGF-1 and IGFBP-3. IGF is not only an important indicator of the safety of the application of growth hormone, but also a reliable basis for adjusting the dose of growth hormone. Some studies have shown that adjusting the dose of growth hormone by IGF results is more effective than the traditional fixed dose. Special note: The above efficacy analysis is only the possible treatment effect of most people, and cannot be absolute, and there are obvious individual differences between different people, and there may be other unchecked disease effects. In addition, personal cooperation is also important, during the medication period, as usual, may also be sick, if often sick, will certainly also affect the efficacy.