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Gonadotropin-releasing hormone ana-logues (GnRHa) are used to treat central precocious puberty. They also are used to delay puberty in short children with a prognosis for impaired adult height. In both cases, growth hormone (GH) treatment is sometimes added. To determine how North American pediatric endocrinologists are using the combination of GH and GnRHa, we searched the National Cooperative Growth Study (NCGS) database and identified 509 patients who were treated with both. Among them were 139 patients with a diagnosis of precocious puberty. Most of these (82%) also had GH deficiency (GHD). Of the 370 patients who did not have precocious puberty, 71% had GHD. There were 200 patients with precocious puberty who were treated with GH but not with GnRHa. The children who were given GH alone (77% of whom had GHD) were much younger than the children who were given both GH and GnRHa (5.7 +/- 2.9 years for those who were not treated with GnRHa vs 9.1 +/- 2.7 years for those who were). Data on both predicted adult height before GH treatment and near- adult height were available for 141 of the patients who were given both GH and GnRHa. There was a statistically significant increase in near-adult height over pre-GH predicted adult height in girls with precocious puberty (5.4 +/- 4.3 cm) and without precocious puberty (3.0 +/- 6.1 cm). There was no statistically significant gain in height for boys who did not have precocious puberty (1.3 +/- 6.8 cm). There were too few boys with precocious puberty (n = 7) to enable meaningful conclusions. In a multiple regression analysis of data on girls who did not have precocious puberty, duration of GH treatment was the most important variable predictive of height gain.gonadotropin-releasing hormone, growth hormone, precocious puberty, idiopathic growth hormone deficiency, organic growth deficiency, idiopathic short stature.

Growth hormone (GH) stimulation tests are considered a prerequisite to clinical trials of recombinant human GH (rhGH) therapy, but the test results may not be predictive of the treatment outcomes with rhGH. We examined the GH stimulation test results as a predictor of the treatment outcome in a cohort of prepubertal subjects in the National Cooperative Growth Study. A standard is proposed in which a diagnosis of GH deficiency is considered appropriate when a patient has significant first-year catch-up growth and that a positive stimulation test result predicts this outcome. With this construct, a traditional interpretation of GH stimulation test results correctly identifies 64% of the rhGH treatment outcomes. The analysis shows an upper limit of diagnostic sensitivity of 82% and a lower limit of specificity of 25% in our study population. The results of our recent studies suggest that the sensitivity and specificity of the current GH stimulation tests are attributable in part to broad intersubject variation in GH clearance, rates of GH elimination, and GH volume of distribution. The combined studies suggest that the use of subject-specific pharmacokinetic parameters will improve the diagnostic interpretation of GH stimulation test results and improve rhGH treatment outcomes.growth hormone stimulation tests, recombinant human growth hormone, pharmacokinetic parameters, maximal stimulated growth hormone concentration.

Objective: To determine whether the height gain during puberty in children with growth hormone deficiency (GHD) who are treated with biosynthetic growth hormone (GH) is similar to that in otherwise healthy children with delayed bone ages and whether the height standard deviation score (SDS), which began to increase before puberty, continues to increase during puberty., Methods: The inclusion criteria included a diagnosis of idiopathic GHD, prepubertal on enrollment in the National Cooperative Growth Study, and spontaneous onset of puberty, as defined by Tanner stage 2 breast development in girls and a testicular volume of at least 3 mL in boys. Near-adult height was judged to have been attained in the subjects who had reached a chronologic age of at least 18 years (females) or 20 years (males) or had reached at least pubertal stage 4 and a chronologic age of at least 14 years (females) or 16 years (males). These subjects constituted group 1. Group 2 was a subgroup of these subjects who met a more stringent criterion for near-adult height; in addition to meeting the above criteria, they had to have attained a bone age of at least 14 years (females) or 16 years (males)., Results: Group 1 consisted of 480 males and 194 females. Group 2 consisted of 153 males and 105 females. In the subjects in group 1, the Tanner pubertal stage 2 was 14.1 +/- 1.5 years in males and 12.6 +/- 1.6 years in females; the bone age at this stage was 11. 9 +/- 1.5 years in males and 10.6 +/- 1.5 years in females; and the height SDS was -2.1 +/- 0.9 in males and -2.4 +/- 0.9 in females. The total height gained during puberty was 22.4 +/- 7.9 cm in males and 17.4 +/- 6.3 cm in females; the percentage of adult height gained during puberty was 13.3% +/- 4.6% in males and 11.3% +/- 4.0% in females; the near-adult height SDS was -1.3 +/- 1.0 in males and -1.6 +/- 0.9 in females; and the target adult height SDS was -0.4 +/- 0.8 in males and -0.5 +/- 0.7 in females. The growth characteristics in the subjects in group 2 were of similar magnitude. In both groups, there was a significant negative correlation between age at the onset of Tanner stage 2 and both the total height gained during puberty and the percentage of adult height gained., Conclusions: The growth characteristics of these subjects were similar to those reported in normal children and in previous reports of the pubertal growth in smaller populations of children with GHD. The height SDS increased in these subjects during puberty, but the target adult height SDS was not attained. This is a strong argument for early diagnosis and treatment in children with GHD to optimize prepubertal growth.

Objective: To evaluate growth rate and adult height with recombinant growth hormone (GH) treatment in girls with Turner syndrome (TS) and predictors of their growth response., Methods: Data on girls with TS who were treated with GH in the National Cooperative Growth Study (NCGS) were evaluated. As of January 1997, there were 2798 girls with TS in the NCGS database, 2652 of whom had not previously received GH. Follow-up data on growth were available for 2475 subjects, and data on adult height were available for 622., Results: The average age of girls with TS at enrollment in the NCGS was 10.1 +/- 3.6 years. These patients had severely short stature compared with that of unaffected American girls (height, 118.5 +/- 16.5 cm; height standard deviation score [SDS], -3.1 +/- 0.9), but their heights were typical of those of American girls with TS (TS-specific height SDS, 0.01 +/- 0.9). Treatment with GH for an average duration of 3.2 +/- 2.0 years resulted in an increase in height SDS of 0.8 +/- 0.7 compared with unaffected girls and of 1.2 +/- 0.8 compared with TS standards. Growth rates increased from 4.0 +/- 2.3 cm/year before treatment to 7.5 +/- 2.0 cm/year after 1 year of treatment. Duration of treatment with GH was the strongest predictor of change in height SDS. After 6 to 7 years of treatment with GH, there was a cumulative change of 2.0 in mean height SDS. The 622 girls who reached adult height were older when they began taking GH. Their mean height gain over pre-GH projected height was 6.4 +/- 4.9 cm after 3.7 +/- 1.9 years of treatment. Their adult height was 148.3 +/- 5.6 cm., Conclusions: Although the response to treatment with GH varied, it was associated with highly significant gains in growth and adult height in girls with TS. Duration of treatment with GH was the most important variable predicting adult height.

Objective: To determine whether treatment of attention deficit hyperactivity disorder (ADHD) with methylphenidate hydrochloride or pemoline diminishes the response to growth hormone (GH) therapy in patients with idiopathic GH deficiency (IGHD) or idiopathic short stature (ISS)., Methods: The National Cooperative Growth Study database was used to identify patients between 3 and 20 years of age with IGHD or ISS and those within these groups who were treated with methylphenidate or pemoline for ADHD. Their growth in response to GH treatment (change in height standard deviation score [SDS]) was compared with that of patients with IGHD or ISS who were not treated for ADHD, by using a stepwise multiple regression analysis., Results: In the IGHD cohort, there were 184 patients who were being treated for ADHD and 2313 who were not. In the ISS cohort there were 117 patients who were being treated for ADHD and 1283 who were not. There was a higher percentage of males being treated for ADHD in both cohorts. In the IGHD cohort, the change in height SDS was positively associated with the number of years of GH treatment, parents' heights, body mass index, and GH injection schedule, and was negatively associated with height SDS at the initiation of GH therapy, age, and maximum stimulated GH level. The use of methylphenidate or pemoline had a negative effect on the change in height SDS, but the magnitude of the effect was small. Similar effects were noted in the ISS cohort, but body mass index and the use of methylphenidate or pemoline had no effect on the change in height SDS., Conclusions: Concurrent ADHD therapy is associated with a slight decrease in the change in height SDS during GH treatment in patients with IGHD but not in those with ISS. Even in IGHD, the magnitude of the effect is small and should not deter the use of such concurrent therapy.

The current doses of recombinant growth hormone (rGH) are two to three times those used in the pituitary growth hormone era. These rGH doses (0.025 to 0.043 mg/kg/d) are similar to or moderately greater than the physiologic requirements. Growth velocity and height gains have been shown to be greater with 0.05 mg/kg/d of rGH than with 0.025 mg/kg/d. Larger doses of GH and early initiation of treatment result in greater heights at the onset of puberty and greater adult heights. Earlier onset of puberty and more rapid maturation, as indicated by bone age, were not observed in children who were given 0.18 to 0.3 mg/kg/wk of rGH. The frequency of adverse events is very low, but diligent surveillance of all children who are treated with rGH is essential.

We analyzed 12-hour serial sampling of growth hormone (GH) levels in two cohorts of short children: 96 children referred to a university endocrine clinic or studied on a research protocol and 825 children in the National Cooperative Growth Study of children treated with exogenous GH. The mean 12-hour GH levels correlated with growth velocity in 60 children with normal height and growth velocity in the university study, and this correlation was stronger in the boys. The testosterone levels also correlated with growth velocity and mean 12-hour GH levels in the boys. The mean 12-hour GH levels were lower in a group of 36 children with idiopathic short stature than in the control subjects, as were the peak GH levels within 1 hour after the onset of sleep and the insulin-like growth factor I levels. In the National Cooperative Growth Study cohort, pooled 12-hour GH levels were lower in the group with idiopathic GH deficiency (n = 300) than in the group with idiopathic short stature (n = 525), but the difference was not significant. The duration of GH treatment was the most significant predictor of change in the height SD score in both groups. Indices of spontaneous secretion of GH were not predictive of the response to GH treatment, nor were the results of provocative GH testing, the responses to GH treatment being similar in both groups over time. We conclude that the results of GH testing must be interpreted for each patient and that several testing modalities may be helpful in finding GH insufficiency that originates at various levels of the somatotropic axis.