Joyce Baptista

Effect of Growth Hormone Treatment on Adult Height of Children with Idiopathic Short Stature

Background Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown. Methods We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups. Results In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls. Conclusion Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children.

Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

Screening girls with turner syndrome: the national cooperative growth study experience

The National Cooperative Growth Study (NCGS) database was examined to determine whether the availability of expert guidelines affected the clinical management of 955 patients with Turner syndrome (TS). Although cardiac and renal evaluations increased in frequency after guideline publication, hearing screenings declined. Although girls with TS show significant cardiac, renal, and hearing problems, screening for these disorders remains inadequate.

Neonatal Hypoglycemia in a Growth Hormone Registry: Incidence and Pathogenesis

OBJECTIVE To examine the characteristics of infants with neonatal hypoglycemia treated with growth hormone (GH) in order to gain insights into factors aiding in the identification of and timely treatment of hypopituitary neonates. STUDY DESIGN The National Cooperative Growth Study (NCGS) database was examined to identify infants with neonatal hypoglycemia started on GH by 6 months of age. 169 infants (100 males, 69 females) were found and their data analyzed for physical characteristics, the presence of other hormone deficits, and the diagnostic methods used. RESULTS Mean +/- SD baseline length standard deviation score (SDS) was -1.5 +/- 1.8. 148/169 infants had hypopituitarism. Twelve had isolated GH deficiency (GHD). Nine had hypoglycemia without hypothalamic or pituitary pathology. Structural central nervous system (CNS) lesions and/or midline facial defects were present in 66/169. 55/100 males had micropenis. Although 158 infants had GHD, only 90 infants had it documented by stimulation testing (80) or a critical sample when hypoglycemic (10). Multiple hormone replacement therapy was necessary in 89% of the hypoglycemic infants. CONCLUSIONS The great majority of these hypoglycemic infants had GHD, usually secondary to hypopituitarism. Over 1/3 had structural lesions of the hypothalamic-pituitary area or midline facial defects. Although lengths may be normal in these infants, physical features such as micropenis or cleft lip and/or palate should suggest pituitary dysfunction as the etiology of their hypoglycemia. A critical blood sample for GH taken during hypoglycemia is a quick and definitive diagnostic tool.

Use of magnetic resonance imaging in short stature: data from National Cooperative Growth Study (NCGS) Substudy 8.

The primary use of magnetic resonance imaging (MRI) in the evaluation of children with short stature (SS) is to discover lesions in the central nervous system (CNS), particularly tumors that may require intervention. MRI has a secondary role in identifying structural abnormalities responsible for growth hormone deficiency (GHD). We examined data from the National Cooperative Growth Study (NCGS) Substudy 8 to determine how American physicians are using MRI in evaluating children with SS. Of the 21,738 short children enrolled in NCGS, 5% underwent MRI during their follow-up. Children who had GH stimulation testing were more likely to have had an MRI than those in whom no GH stimulation test was performed (19% vs 2%, p <0.0001). Moreover, children diagnosed with severe GHD (maximum GH <5 ng/ml) were more likely to have an abnormal finding on MRI. Of these patients, 27% demonstrated an abnormality as compared to 12% and 12.5% in patients with partial GHD and normal GH stimulation test results (>10 ng/ml), respectively. Abnormalities unrelated to the hypothalamus or pituitary represented 30% of these findings, while disorders in pituitary anatomy, including pituitary hypoplasia, pituitary stalk interruption, and ectopic posterior pituitary, represented an additional 30% of abnormal MRI examinations. CNS tumors comprised 23% of abnormal findings in these patients. We conclude that MRI provides significant value in the evaluation of children with SS, by identifying CNS tumors associated with growth failure as well as anatomical abnormalities of the pituitary. These findings are useful in confirming the diagnosis of GHD in children and identifying potential candidates for continued GH replacement in adulthood.

Long-Term Growth Hormone Treatment of Growth Retarded Children With Chronic Renal Insufficiency (CRI) |[dagger]| 1798

One hundred twenty-five patients were enrolled in a study of growth retarded pre-pubertal (at baseline) children with CRI and were randomized to recieve either rhGH 0.5 mg/kg/day SC or an equal volume of placebo for two years. After two years all patients received rhGH. Treatment was paused in 24 children after reaching mid-parental target height percentile, of whom 17(71%) required re-initiation of rhGH because of a substantial decrease in standardized height. Long-term (5 year) treatment of 35 children led to a significant (p<0.0001) improvement in standardized height from -2.8 at baseline to -0.9 at 5 years. Adult height potential was not adversely impacted with a Δ height age minus Δ bone age at 5 years of +0.3 (N=21). The mean calculated creatinine clearance decreased from 36.2 ± 19.0 mL/min/1.73m2 at baseline to 27.2 ± 18.8 mL/min/1.73m2 at 5 years (p=.0007) which would be consistent with the natural history of CRI children. There was a small increase in the median fasting and 2 hour post-prandial plasma insulin levels during treatment. Development of avascular necrosis of the femoral head, a known compliction of renal osteodystropy was observed in several patients. Presence of AVN was noted on hip x-rays prior to initiation of rhGH in three patients. Because baseline x-rays were not available for most patients this finding requires further investigation. Forty-eight patients had renal transplants and 42 were treated with growth hormone prior to transplant. Thirty patients (23M, 7F) received at least 2 years of rhGH therapy before transplant. Their mean±SD Ht SDS was -2.8± 0.9 at baseline and -1.2 ± 1.2 at transplant. This is a significant (p<0.0001) mean improvement of 1.6 ± 1.0 in Ht SDS after a mean of 4.3 ± 1.7 yr. of rhGH therapy. Long-term rhGH treatment in children with CRI improves the potential of children with CRI achieving target adult height.

Effects of High Dose rhGH Therapy in Adolescent Children with GH Deficiency: A Randomized, Multicenter Study • 460

GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, pubertal GH-deficient children have been dosed on a standard per kg body weight basis similarly to prepubertal children. This study was designed to compare the efficacy and safety of conventional (Group I (GI), 0.3 mg/kg.w) vs high dose rhGH Rx (Group II (GII), 0.7 mg/kg.w), in GH-deficient adolescents treated with rhGH for at least 6 mo. 97 children with evidence of GH deficiency (poor linear growth, peak GH to stimuli < 10 μg/L, organic and idiopathic), were recruited. The groups were matched for sex (I:42M, 7F; II: 41M, 7F), age (I: 14.0±1.6 (SD) yrs; II: 13.7±1.6), height SDS (I: -1.4±1.1; II:-1.2±1.1), bone age (BA) (I: 13.2±1.3 yrs; II: 13.1±1.3) and etiology, maximum stimulated GH, previous growth rate and mid-parental target height (Ht). All were in puberty (mean: Tanner Stage 3). Differences from baseline (Δ) were available at 12, 24 and 30 mo. The Δ growth velocity (cm/y) at 12 mo: -0.3±2.5 (I), +1.3±2.8 (II), p=0.005; at 30 mo: -3.8±2.9 (I),-2.0±3.4 (II), p=0.07; Δ Ht (cm): 12 mo: 8.2±2.3 (I), 9.9±2.1 (II), p=0.0004; 30 mo: 18.6±4.7 (I), 21.8±4.8 (II), p=0.02; Δ Bailey-Pinneau predicted Ht (cm): 12 mo: 1.1±4.6 (I), 3.3±4.9 (II), p=0.03; 30 mo: 4.4±5.4 (I), 7.7±6.8 (II), p=0.17. Δ IGF-I: 12 mo: 131±238 μg/L (I), 175±317 (II), p=0.89; 30 mo: 257±255(I), 329±411 (II), p=0.92. No differences in Δ BA were detected between groups at any interval: 30 mo: 2.6±1.2 (I), 2.6±1.1(II), p=0.94. In boys treated ≥2 yrs, the Δ Ht was 4cm greater in the high-dose group. High dose rhGH was well tolerated with no difference in HbA1c or glucose concentrations between groups. Plasma insulin concentrations were higher in GII (p=0.01). In summary: Preliminary analysis shows that as compared to conventional treatment, high dose rhGH Rx in adolescents: 1-increased Ht and Ht SDS scores significantly; 2-did not advance skeletal maturation; 3-appeared to be well tolerated and safe. We conclude: High dose rhGH Rx improves the final adult Ht gain in GH-deficient patients in puberty, without increasing the rate of bone maturation.

GH TREATMENT IN IDIOPATHIC SHORT STATURE: INFLUENCE OF PUBERTY AND SEX ON SKELETAL MATURATION AND GROWTH RESPONSE

We treated 121 patients with height below -2 SDS for age and stimulated GH > 10 ng/mL (ISS) with GH for up to 5 years. The majority of these patients achieved improved growth rate, height SDS, and predicted adult height with GH therapy prior to puberty. The age of onset of puberty in these GH-treated ISS patients was not advanced However, data suggests that GH-treated patients may transit puberty faster and not achieve their predicted gains in adult height. We compared 92 GH-treated ISS patients with 252 untreated normal children followed longitudinally whose height was ahove -1 SDS (NL ≥ 1) for age or below -I SDS (NL < -1) for age. The change in Pels method bone age per year (ΔBA/ΔCA) arid the change in Bayley-Pinneau predicted adult height per year (ΔPHt/ΔCA) were compared before puberty (BA ≤11yo in ♂, ≤9yo in ♀) and during puberty (BA ≥ 12yo ♂, ≥ 10yo ♀):We conclude that GH-treated ISS ♂ progress through puberty faster, and do not continue to increase PHt. Early GH treatment, increased GH dosage, or prolongation of puberty may be needed to achieve target increases of final height in ISS boys.

SKELETAL MATURATION AND GROWTH DURING PUBERTY IN PATIKNTS WITH GROWTH HORMONE (GH) DEFICIENCY OR IDIOPATIHC SHORT STATURE TREATED WITH GH

Patients with GH deficiency or idiopathic short stature (ISS) demonstrate improved growth rate and predicted adult height with GH therapy prior to puberty. However, some studies have suggested that there is an increased rale of pubertal development and skeletal maturation with GH therapy during puberty. We studied patients with GHD and ISS enrolled in multicenter trials in which rhGH therapy (0.3 mg/kg weekly) was initiated before puberty. Bone ages (BA) were determined centrally by the FELS method. The table below shows the mean and (n) for change in BA, change in height SDS adjusted for bone age (HtSDSBA), and change in Bayley-Pinneau (BP) predicted adult height, each divided by change in chronological age (CA). Patients were grouped according to pre-pubertal or pubertal bone ages. Bone ages taken at least 1 yr apart were used.CONCLUSIONS: The yearly change in height SDSBA was positive in all groups. All group improved BP predicted height with the exception of pubertal male ISS patients, suggesting the importance of early treatment for these patients.