Growth hormone (GH) is a protein hormone produced by the anterior pituitary growth hormone cells and can exist in the form of monomers, dimers or aggregates in the circulation. 80% are 22KD monomers containing 191 amino acids and 20% are 20KD monomers containing 176 amino acids. It has a great influence on the function of heart, kidney and bone, and the metabolism of sugar, fat and protein in human body.
In 1958, GH extracted from human pituitary gland was used to treat patients with growth hormone deficiency (GHD), but although it was effective, it was not easy to obtain and the yield was very small, which could not meet the needs of patients. It was not until 1985 that human growth hormone made by recombinant gene technology could be produced in large quantities and better applied in clinical practice.
Recombinant human growth hormone (rhGH) has been widely used in the treatment of pituitary GHD, and has achieved better efficacy and experience. With the continuous research on the etiology 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 chronic renal failure and adjuvant treatment of precocious puberty.
On June 10, 2003, the FDA approved the use of rhGH for the treatment of idiopathic short stature (ISS), the cause of which is unknown and may be due to a combination of underlying factors.
It is a polygenic disease that may be due to a combination of several potential factors, including inadequate or disrupted GH secretion, poor GH activity, abnormal or mutated GH receptors, and relative deficiency of insulin-like growth factor-1 (IGF-1). With the improvement of biochemical and genetic testing technology, the etiology of ISS may be gradually found in the future.
Regarding the incidence of ISS, there are very few reports in the literature. In Taiwan, a survey was conducted on school students, and it was found that among the causes of pathological dwarfism, ISS accounted for 7.9%; GHD 7.9%; precocious puberty 3.2%; bone development disorder 2.3%; intrauterine growth retardation 1.4%; congenital ovarian hypoplasia 1.4%; chromosomal abnormalities 0.8%; and others 1.4%.
The diagnostic criteria for ISS according to literature reports can be summarized as follows:
1, height below the normal mean value of 2.25s;
2, normal birth height and body mass, normal body proportions;
3, growth rate is close to normal or slightly slower;
4.Bone age is normal;
5.Pubertal development is Tanner I and II stage;
6, GH peak value >10ng/ml in GH excitation test results of two drugs;
7, Exclude other causes of short stature (chronic systemic diseases, skeletal and endocrine system diseases, chromosomal diseases, etc.).
The aim of treatment is to improve the patient’s final height and the psychological stress caused by short stature, and to improve and enhance the quality of life. The more recognized treatment is with rhGH, and the improvement of final height has a certain relationship with the dose. the FDA conducted a multicenter, double-blind, randomized control group in the United States to treat 38 cases of ISS, aged 9-15 years for females and 10-16 years for males, with a height of s-2.8 before treatment. rhGH dose was 0.22 mg/(kg.week), subcutaneous injection in 3 times a week, and the average treatment The mean treatment time was 4.4 years, and the mean age at the end of treatment was 18.8 years.
The mean age at the end of treatment was 18.8 years. The height after treatment was s-1.8. 33 cases in the control group had s-2.3 after treatment, and there was a significant difference between the two groups. Results Final height in the treated group improved by (0.51±0.2)s, or 3.7 cm, compared to the baseline predicted height, with a final height growth range of 2.8 to 5.0 cm. no acceleration of bone maturation or early puberty was seen. The extent of height growth was observed in Europe by treating ISS with the same method at different doses for a mean treatment period of 2 years. Group 1 (78 cases) had rhGH of 0.24 mg/(kg.week) and height growth of 5.4 cm, raising height by 1.6s; group 2 (78 cases) started treatment with a dose of 0.24 mg/(kg.week) and after 1 year the dose was increased to 0.37 mg/(kg.week) and height growth was 6.7 cm; group 3 (83 cases) started with a dose of 0.37 mg/(kg.week ), and the final height growth was 7.2 cm, an improvement of 1.9s.
There was no hyper-rapid increase in bone age during the treatment period. The results showed that their height growth rate was dose dependent, and a dose of 0.37 mg/(kg.week) was more effective than a dose of 0.24 mg/(kg.week), so the recommended optimal dose is 0.37 mg/(kg.week) (0.4 mg is equivalent to 1.2 U) for a minimum of 6 months and preferably 2 years. Treatment was discontinued when the growth rate was <2 cm/year and final height assessment was performed. Only one case each of arthritis and femoral head slippage with drug-related adverse effects was reported in their study, and no other adverse effects were found.
Kamp took a randomized approach to 35 cases of ISS, divided into 17 cases in the treatment group and 18 cases in the control group for a total duration of 5 years, with rhGH doses of 1.5 IU/(m2.d) and 3.0 IU/(m2.d) in the first year and an increased dose of 6.0 IU/(m2.d) for at least 2 years if efficacy waned, and discontinued when puberty appeared. The general course of treatment for 3 to 4 years showed a significant improvement in mean height s, from s-2.6 to s-1.3 for those with 2 years of treatment, with no change in the control group.
The most common adverse effect of rhGH is the effect on pituitary-thyroid axis function. Approximately 30% of patients have subclinical hypothyroidism with low thyroid function and reduced serum T4 without changes in TSH concentration, requiring timely thyroid hormone supplementation. About 5%-30% may produce rhGH antibodies, and individuals may develop idiopathic intracranial hypertension with clinical headache, most likely due to cerebrospinal fluid transfer caused by rapid correction of GHD by rhGH.
A small number of patients have abnormal liver function, which can be recovered after stopping the drug. This is followed by localized redness and swelling of the injection, which usually subsides in 2-3 d, or 1 to 2 months. Foreign reports of children with ISS treated with rhGH for 5 years, closely tested blood thyroid hormone, blood lipids, fasting and 2h postprandial glucose, all maintained normal levels, fasting and postprandial insulin levels increased from the low limit of normal to normal levels, it was pointed out that 5 years of treatment with rhGH for ISS treatment did not reveal abnormal changes in metabolic indicators related to clinical.
More domestic literature has reported on the efficacy of applying domestic rhGH in the treatment of GHD. 63 cases of IGHD in 3 hospitals were treated with rhGH at a dose of 0.1 IU/kg for 6 months, with a height increase of (7.0±1.6) cm and a growth rate increase of (14.0±3.2) cm/year [before treatment (2.9±0.9) cm/year]. The Department of Endocrinology, Peking Union Medical College Hospital treated idiopathic GHD dwarfism with rhGH at a dose of 0.1 IU/(kg.d) for 6 months in skeletal age 13-17 years old, and the results showed that rhGH still promoted the growth of IGHD height in skeletal age 13-17 years old.
In the past 3 years, Beijing Children’s Hospital also applied domestic rhGH to treat more than 200 patients with GHD, congenital ovarian syndrome and short stature due to precocious puberty, and achieved good results. Recently, 5 cases were treated with ISS, aged 8.5-10.2 years, with height below 2s (mean -2.6s), bone age 75% lower than the actual age, pubertal development Tanner stage I, GH excitation test GH peak >10ng/ml, rhGH dose 0.15IU/(kg.d), after 6 months of observation, the height improvement s was 1.3 ( mean of -1.3). No adverse effects were found during the treatment.