Diagnosis and growth hormone (GH) therapy in children with GH deficiency: experience in King Chulalongkorn Memorial Hospital, Thailand.

BACKGROUND: Diagnosis of growth hormone deficiency (GHD) needs both clinical and biological aspects such as auxological data and GHprovocative tests, and active metabolites of GH including IGF-I and IGFBP-3. In GHD children, rhGH has been used worldwide with minimal serious side effects. The aims of the present study were to describe the experience in King Chulalongkorn Memorial Hospital regarding diagnosis and treatment with rhGH in GHD children. MATERIAL AND METHOD: Clinical data of 173 short children was retrospectively reviewed. Two GH provocative tests used in the present study were insulin tolerance test (ITT) and clonidine test. To make the diagnosis of GHD, the children had to fail both GH provocative tests (peak GH < 10 ng/ml). Baseline clinical data, IGF-I, and IGFBP-3 were compared between the group with true positive test and the group with false positive test. Thirty-five children with GHD, who had been treated with rhGH, were evaluated in terms of growth response, changes of IGF-I SDS and the relationship between these parameters. RESULTS: From the present study, ITT could diagnose GHD with true positive 57% and false positive 43% and clonidine could diagnose with true positive 67% and false positive 33%. Clinical data including chronological age, bone age, HtSDS, WtSDS, IGF-I SDS, and IGFBP-3 SDS were not different between the true positive and false positive group. rhGH with a mean dose of 29.3 +/- 4.6 microg/kg/day increased height velocity (HV) from 3.9 +/- 2.5 to 9.3 +/- 2.5, 8.1 +/- 1.5, 7.2 +/- 2.2, 6.8 +/- 2.2, 7.6 +/- 2.4, and 6.5 +/- 1.8 cm/yr after 6 months, 1, 2, 3, 4, and 5 years after treatment, respectively. This also improved HtSDS during treatment and brought the HtSDS into the target range after 3 years of treatment. At the end of the first year of treatment, the difference of IGF-I SDS (DeltaIGF-I SDS) > or = 1 could predict a good response (DeltaHtSDS > or = 0.5) with sensitivity of 88.9% and specificity of 60% respectively. At the end of the second year, DeltaIGF-I SDS > or = 1 could predict a good response with sensitivity and specificity of 100% and 29%, respectively. CONCLUSION: From the present study, the authors demonstrated the investigation and treatment practices of short children with GHD. The growth response is satisfactory even with a lower dose than suggested. In addition, measurement of IGF-I and IGFBP-3 cannot be used in diagnosing GHD but can predict the height outcome at least by the first 2 years of the treatment. However long-term outcome need to be clarified.

Bone mineral density and body composition in Thai Precocious Puberty girls treated with GnRH agonist.

Treatment of true Precocious Puberty (PP) with GnRH agonist can improve final adult height by suppressing gonadotropin and sex hormone levels that delays the fusion of long bone epiphyseal growth plates. However, deprivation of estrogen may affect the acquisition of peak bone mass, especially in individuals with low calcium intake. Ten Thai girls with idiopathic true PP were evaluated for Bone Mineral Density (BMD) and body composition by DXA scanner (Hologic, Inc) before and after GnRH agonist therapy for 1 year. During treatment, all children were allowed to consume a normal diet without extra calcium supplementation. In addition, serum calcium, phosphate, alkaline phosphatase and osteocalcin were also measured. The results showed that GnRH agonist could improve predicted adult height from 149.4 +/- 5.4 to 153.6 +/- 6.8 cm (p < 0.001). Serum osteocalcin, representing the bone marker formation, decreased from 184.2 +/- 66.7 to 108.6 +/- 35.3 ng/mL (p = 0.012) However, the treatment had no negative effects on BMD lumbar spine and total BMD but increased percentage of fat mass from 25.7 +/- 5.2 to 31.6 +/- 5.5%. (p =0.007). In conclusion, treatment with GnRH agonist in Thai girls with true PP for 1 year can improve PAH without negative effects on BMD but a longer period of treatment needs to be studied.

Final adult height in "early normal pubertal girls" treated with gonadotropin releasing hormone agonists.

Gonadotropin releasing hormone (GnRH) agonist has been used worldwide for the treatment of central precocious puberty. However, the results on final adult height (FAH) are discrepant in various studies especially in girls with normal early puberty. Fourteen girls with normal early puberty who were treated with depot GnRH agonists 3.75 mg intramuscular (i.m.) monthly for a mean period of 1.5 +/- 0.4 yr were retrospectively studied. The chronological age and bone age at the beginning of treatment were 9.9 +/- 0.7 yr and 12.6 +/- 0.9 yr, respectively. When the treatment was stopped, all the girls were followed-up until they reached their final adult heights. The results showed that the mean FAH was 154.0 +/- 6.9 cm, which was not significantly different from the predicted adult height (PAH) at start of treatment, 153.1 +/- 6.2 m. All the girls were divided into 2 groups. Group A was girls who had FAH-PAH at the start of treatment > or = 1.5 cm and group B, FAH-PAH at the start of treatment < 1.5 cm. The authors found that only the duration of treatment was different between these 2 groups, 1.7 +/- 0.3 yr in group A and 1.3 +/- 0.3 yr in group B (p = 0.015). In conclusion, GnRH agonist cannot improve the final height outcome in girls with normal early puberty. However, a longer period of treatment may improve the height prognosis.

Basal luteinizing hormone/follicle stimulating hormone ratio in diagnosis of central precocious puberty.

BACKGROUND: Precocious puberty is characterized by breast development in girls prior to 8 years old and may have acne, adult odor, growth spurt and menstruation. Conventionally, gonadotropin releasing hormone (GnRH) stimulation test is a gold standard for diagnosis of central precocious puberty but it is a time-comsuming procedure that is not practical on an out patient basis. OBJECTIVE: To evaluate the basal luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio in diagnosis of central precocious puberty in order to save time and cost. SUBJECTS AND METHOD: The GnRH stimulation tests were performed on 51 girls with breast development before 8 years old. The 51 girls were divided into 2 groups, 24 girls with central precocious puberty (CPP) and 27 girls with premature thelarche (PT), and the clinical data and GnRH stimulation tests data were compared between the 2 groups. The authors also compared the clinical data and GnRH stimulation tests data between 13 girls with PT and 12 girls with thelarche variants (TV) who developed puberty approximately 1 year later as confirmed by GnRH stimulation test. RESULTS: Girls with CPP had a large bone age and chronological age ratio and advancement of breast staging. Girls with TV had a greater level of basal luteinizing hormone (LH), peak LH and 120 min estradiol than girls with PT. Basal luteinizing hormone and follicle stimulating hormone (FSH) ratio greater than 0.2 can be used to diagnose CPP with 75 per cent sensitivity, 85 per cent specificity, 82 per cent positive predictive value (PPV) and 82 per cent negative predictive value (NPV). CONCLUSION: Girls with CPP have a basal LH/FSH ratio greater than 0.2 and this can be used as a cut-off point for the diagnosis CPP.

Measurement of IGF-1, IGFBP-3 and free IGF-1 levels by ELISA in growth hormone (GH) deficient children before and after GH replacement.

Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels reflect the growth hormone (GH) status. A few percent of IGF-1 circulate in a free form which is believed to represent the IGF biological activity. We retrospectively studied the changes of serum IGF-1, serum IGFBP-3, and plasma free IGF-1 levels in growth hormone deficient (GHD) children before and after treatment with recombinant human growth hormone (rhGH) for a period of 6 months and 1 year. Twenty-one GHD children (16 boys and 5 girls) who had the mean chronological and bone ages of 7.7 +/- 0.7 and 4.8 +/- 0.6 years, respectively, were treated with a mean rhGH dose of 11.66 +/- 0.42 U/m2 body surface area/week. Serum IGF-1 level increased from 162.5 +/- 42.9 ng/ml before treatment to 252.8 +/- 49.5 ng/ml (p = 0.007) and 282.7 +/- 86.9 ng/ml after treatment for 6 months and 1 year, respectively. Plasma free IGF-1 also increased from 0.38 +/- 0.30 ng/ml before treatment to 1.21 +/- 0.30 (p = 0.001) and 1.17 +/- 0.42 ng/ml after 6 months and 1 year of treatment. However, serum IGFBP-3 did not significantly increase after treatment. In addition, the free/total IGF-1 ratio decreased after treatment with rhGH. The height velocities at 6 months and 1 year after treatment were negatively correlated with plasma free IGF-1 before treatment. In conclusion, therefore, plasma free IGF-1 levels could serve as a good predictor of growth hormone responses. Furthermore, their circulating levels would be modified by serum IGF-1 status, and possibly, IGFBP-3 protease activity.

Sitting height and subischial leg length of Thai schoolboys in Bangkok.

Anthropometry is an important way to evaluate a child's growth pattern. The measurement of sitting height helps to define body proportion. Every country should have its own normal data and use it as a national reference. The measurements of standing height, sitting height, and weight were performed in 2,650 schoolboys, aged 11-18 years, and then the subischial leg length, and the sitting height/height (SH/H) ratio were calculated. The results were compared to the data of British boys studied by Tanner et al. The authors found that, in boys aged less than 15 years, the sitting height in Thai schoolboys was similar to that of British boys but the subischial leg length was longer. However, the sitting height and subischial leg length in Thai schoolboys became shorter than that of British boys after 15 years of age. This resulted in shorter adults when compared with British boys. In addition, the SH/H ratio in Thai schoolboys was the same as that in British boys when they reached the near final height. More data in both genders should be studied in order to construct our national references.

Insulin-like growth factors and their binding proteins in children with IDDM.

The structure of insulin-like growth factor (IGF), especially IGF-I, and its receptor is similar to that of insulin. Therefore, the changes of IGFs and IGF-binding proteins may be related to glucose homeostasis in children with insulin dependent diabetes mellitus (IDDM). Sixty-three fasting blood samples of 21 children with IDDM attending 3 consecutive diabetic clinics were studied. The HbA1c progressively decreased from the 1st to the 3rd visit. IGF-I levels, both total and free forms, were not significantly different from that of control. IGFBP-3 levels in 3 visits (3406+/-305, 3376+/-252, and 2406+/-247 ng/mL) were significantly lower than that of control (5020+/-415 ng/mL) with the p value of 0.007, 0.002, and < 0.001 respectively. IGFBP-1 levels in the 1st and 2nd visits (102.1+/-12.9 and 114.1+/-14.5 ng/mL) were significantly higher than that of control (60.1+/-15.2 ng/mL) with the p value of 0.03 and 0.01 respectively, but not in the 3rd visit. IGF-I level had a positive correlation with IGFBP-3 (R=0.56, p=0.01) and free IGF-I (R=0.53, p=0.01). Free IGF-I had a negative correlation with IGFBP-1 (R=-0.64, p=0.01). IGF-II at the 15 visit had a negative correlation with HbA1c (R=-0.49, p=0.047). The authors found no correlations between IGF-I, IGFBP-3, free IGF-I, IGFBP-1 and HbA1c in the study. The patients' height SDS followed the genetic height potential. It was, therefore, postulated that a near normal free IGF-I level in diabetic children resulted from a balance of interaction between IGFBP-1 and IGFBP-3 to total IGF-I in order to keep the normal metabolic status as much as possible.