Long-term large doses of adrenal glucocorticoids may cause children's height growth to be significantly slowed down or even completely stagnated, but there is currently very little clinical research data [1-4]. This study conducted a preliminary analysis on the inhibition of long-term use of adrenal glucocorticoids on the secretion of human growth hormone (hGH) in children and adolescent patients and the efficacy and safety of recombinant human growth hormone (rhGH) treatment in some children.
object and method
object
was used as the study subjects for 12 children diagnosed and treated by Peking Union Medical College Hospital between September 1999 and November 2009, including 2 males and 10 females; mean age (10.4 ± 1.2) years (7.2~15 years old). All included patients met the following criteria: (1) Taking adrenal glucocorticoid (prednisone) for more than 6 months, the primary disease was remission for at least 12 months (no obvious clinical symptoms, and all relevant laboratory tests were normal); (2) The dosage of prednisone is 0.5~2.0 mg/(kg·d). Among them, there were 7 cases with dosages of 0.5 to 1.0 mg/(kg·d), and 5 cases with dosages of 1.0 to 2.0 mg/(kg·d), and the course of treatment was from 6 to 18 months, and the medication was continued or interrupted. The primary disease was nephrotic syndrome 6 cases (1 male and 5 female), 1 case of systemic lupus erythematosus (female), 3 cases of skin disease (allergic disease) (1 male and 2 female), and 2 cases of chronic idiopathic thrombocytopenic purpura (female).
Growth and development status evaluation
Regularly measure the height and weight of the children, calculate the body mass index (BMI), growth rate, height standard deviation score (standard decoration scoring, SDS), bone age and evaluate youth development. BMI = weight (kg)/height² (㎡), height SDS = (patient's height - mean of the height of normal children of the same gender and age)/standard deviation of height standards for normal children of the same region, bone age counting method (calculate the number of ossification center appearance and epiphyseal fusion and compare it with the corresponding standards to obtain bone age) and calculate bone age, and use the degree of sexual characteristics development (breasts/testicles, pubic hair) to perform staging of pubertal development (Tanner stage)
hGH and insulin-like growth factor-1 level determination
Two hGH excitation tests were performed on each child (levodopa + insulin hypoglycemia or arginine excitation test). In two hGH excitation tests, the serum hGH peak value of 10.0 ng/ml was used as hGH secretion disorder. The inter-batch and intra-batch variation coefficients (CV) of serum hGH level determination (radioimmunotherapy) were 5.96% and 5.82%, respectively. The blood insulin-like growth factor 1 (IGF-1) level (enzyme-linked immunoassay, US DSL ELLSA kit), and the inter-batch and intra-batch CVs were 7.0% and 8.5%, respectively.
rhGH treatment and evaluation
With the written informed consent of the child's parents or guardian, 7 of the children with stable primary disease were treated with subcutaneous injection of rhGH after six months of discontinuation of prednisone. The dose was 0.1U/(kg·d), once a day, and the injection was 6 to 12 months, and their efficacy and safety were evaluated.
Statistical processing
All data were analyzed using SPSS11.0 statistical software. The description of the metrology data is expressed by the mean ± standard deviation, the statistical description of the counting data is expressed by the composition ratio, and the comparison of the data between groups is t-test, and the difference is statistically significant.
Results
Effect of prednisone treatment on the growth and development of children
The height SDS of children before prednisone treatment was -1.5±0.1, and the growth rate was (3.7±1.2) cm/year (n = 11); the growth rate was significantly slowed during prednisone treatment, with an average of (1.2±0.3) cm/year; among them, the SDS of the body after half a year of prednisone treatment was -1.7±0.2 (n = 12), and the growth rate was (2.0 ±1.0) cm/year (n=10), the height growth rate was significantly lower than before prednisone treatment (P0.05); after one year, it was divided into -2.5±0.3 and (1.0±0.7) cm/year (n=11), and the height growth rate was also significantly lower than before prednisone treatment (P0.05). After half a year of discontinuation of prednisone treatment, the height SDS of the child was -2.1±0.2, and the growth rate was (3.3±0.5) cm/year (n=11), which significantly improved compared with the growth rate after 1 year of prednisone treatment (P 0.05).Six children with developmental data before follow-up, three of which were in Tanner stage II and had no progress during prednisone treatment; another female child only started pubertal development at the age of 16; the remaining two entered the pubertal development period between the ages of 12 and 13.
Effect of prednisone treatment on hGH secretion level in children
12 children were subjected to 2 hGH excitation tests (levodopa excitation test + insulin hypoglycemia test or arginine excitation test). Among them, 10 of them performed hGH peaks in 2 excitation tests were all less than 10ng/ml, indicating that the secretion of hGH in the children was significantly affected during the treatment with prednisone. The incidence of abnormal hGH secretion in children with prednisone course > 12 months was significantly higher than that in children with 6 to 12 months of treatment (P 0.05) (Table 1). The incidence of abnormal hGH secretion in children with prednisone doses of 0.5~1.0 mg/(kg·d) and 1.0~2.0 mg/(kg·d) was 71.4% and 80.0%, respectively, and there was no significant difference between the two (P <>
rhGH on children with growth disorder caused by prednisone
7 children were treated with rhGH of 0.1U/(kg·d) after half a year of discontinuation of prednisone. After half a year of treatment, the growth rate of the children increased from (2.2±0.1) cm/year to (7.8±0.5) cm/year (P 0.05). Among them, the growth rate of 5 children reached (6.9±0.4) cm/year after one year of treatment. The height SDS and IGF-1 levels of children six months and one year after treatment were significantly higher than before treatment (P0.05) (Table 2).
rhGH treatment safety
During the treatment process, one patient had a mild headache, but it was completely relieved after 3 days. The other children had no obvious discomfort complaints, liver and kidney function and urine routine were normal, while the children's primary disease was stable, and the relevant indicators remained stable.
Discussion on
Currently, the phenomenon of glucocorticoid treatment has caused the significant slowdown or even stagnation of children's height growth. The cases selected in this study were all taken prednisone for more than half a year. The primary disease condition has stabilized, and all test indicators related to the primary disease have returned to the normal level of children of the same age, so the impact of the primary disease on hGH can be initially ruled out. Among the 12 children, 10 children had abnormal secretion of hGH in both growth hormone stimulation tests; in addition, the effect of adrenal glucocorticoid on hGH secretion is closely related to the course of treatment for taking glucocorticoids. After stopping the adrenal glucocorticoid, the incidence of abnormal hGH secretion decreased significantly. However, due to the small number of cases, the results of this study are different from those of Zuo Ruiping [5], so further study is needed on the effect of taking different doses of prednisone on hGH secretion in children.
This study results show that prednisone causes height growth disorders in children, and abnormal hGH secretion caused by pharmacological doses of prednisone may be one of the main reasons. Prednisone can increase blood sugar levels, thereby inhibiting the hGH secretion level in the children; in addition, prednisone can cause the children to be excited, sleep quality decreases and mood changes, which can cause the hGH pulsed release rhythm to be disordered. Leal-Cerro et al. [1] observed the hGH secretion in patients with Cushing's syndrome and found that the hGH secretion level caused by growth hormone releasing hormone (GHRH) in the patient group was significantly lower than that in the normal group. From this, it can be inferred that adrenal glucocorticoid affects the secretion of GHRH through negative feedback inhibition of the hypothalamic-pituitary axis, thus ultimately affecting the secretion of hGH.
Loke et al. [2] gave rhGH treatment to 8 children with nephrotic syndrome who had recurrent attacks and had a course of disease between 6.0 and 11.5 years, which significantly accelerated their growth and development. This study's clinical observations of 7 children at 6 to 12 months also confirmed that rhGH treatment can significantly improve the growth and development delay caused by glucocorticoids, and significantly accelerate the linear growth of the children. However, the sample size needs to be increased and further research is needed. As for the theory proposed by some scholars that combined the application of adrenal glucocorticoids and rhGH to combat adverse reactions such as height growth and youth development delays, as well as osteoporosis and protein loss caused by adrenal glucocorticoids [5], further sign-on research is still needed.
To sum up, long-term use of adrenal glucocorticoid treatment can cause hGH secretion in adolescent children, and discontinuing adrenal glucocorticoid treatment can restore it to normal after half a year; rhGH treatment can improve the growth rate of such children and improve their development status.
References
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[2] Loke KY, Yap HK, Zhou X, et al. Effect and safety of one year of growth hormone therapy in steroid-dependent nephritic syndrome [J]. Pediatrics, 1997, 130(9):793-799.
[3] Stratakis CA. Cortisol and growth hormone:clinical implications of a complex, dynamic relationship [ J], Pediatr Endocrinol Rev, 2006, 3 (suppl 2):333-338.
[4] Canton A, Trainer PJ, Martinez-Caceres E, et al. Effect of growth hormone in an experimental model of protein hyperca-tabolism induced by glucorticoids [J]. Horm Metab Res, 2006, 38(9): 556-562.
[5] Zuo Ruiping, Cao Li. Effects of long-term adrenal corticosteroids on growth hormone secretion in children [J]. Journal of Practical Pediatric Clinical Clinical, 2004, 19 (8): 648-649.
