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Aim: A recent secular trend towards earlier thelarche has been suggested. The aim of this study is to examine normative ages of thelarche and menarche in contemporary US females., Methods: Trained physicians documented Tanner breast stage by observation in a cross-sectional cohort. Age of menarche was self-reported. The subjects were healthy female children and adolescents. The mean age of thelarche was determined by probit analysis and the mean age of menarche was determined by using a normal time-to-event model., Results: Mean age of thelarche was 9.7 years among 610 females aged 3.0-17.9 years (70% non-Hispanic Caucasian (NHC), 14% African-Americans, 7% Hispanic, 9% "other"). The mean age of menarche was 12.8 years for NHC, with African-Americans having menarche 0.6 years earlier., Conclusions: Thelarche occurred earlier than recently reported, while age of menarche remained unchanged, this supported a persistent secular trend towards earlier thelarche but stable age of menarche. This suggests that the observed thelarche is gonadotropin-independent or the tempo of pubertal advancement has slowed.

The GHMonitor, introduced in 1998, monitors demographics and outcomes in children treated with Saizen (somatropin [recombinant hGH for injection]). Follow-up data are available on 697 patients. The proportion of male to female patients receiving growth hormone (GH) treatment was 67:33. Severity of the height deficit present at enrollment varied by diagnosis with patients with Turner syndrome being shortest [height standard deviation score (SDS)=-3.7+/-1.7] and those with organic GH deficiency the least severely stunted (height SDS=-1.9+/-1.5). Forty-eight patients (6.9%) discontinued participation in the registry. The most common reason for discontinuing GH was completion of growth; the second was family relocation. There were 53 adverse events reported in 33 patients in 1977 patient-years of followup. Most were self-limited but 13 were serious, and 5 resulted in discontinuation of treatment. Data from The GHMonitor provide a real world glimpse of current North American GH treatment practices.

Long-term GH replacement therapy is indicated for children with growth failure due to GH deficiency (GHD). We evaluated the feasibility of administering a long-acting GH preparation [Nutropin Depot (somatropin, rDNA origin) for injectable suspension] to prepubertal children with GHD by examining pharmacokinetic and pharmacodynamic response parameters after single or multiple doses. Data were collected from three studies involving 138 children treated with Nutropin Depot 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. Twenty-two patients underwent intensive sampling to estimate mean peak serum GH concentrations (C(max)) and time to achieve C(max) for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. C(max) and area under the curve were approximately proportional to the dose administered. Fractional area under the curve data indicate that at least 50% of GH exposure occurs during the first 2 d after administration. Serum GH levels remained above 1 microg/liter for 11-14 d. IGF-I levels remained above baseline for 16-20 d, but increases were not proportional to dose. After multiple doses over a 6-month period, peak and trough concentrations showed no progressive accumulation of GH, IGF-I, or IGF binding protein-3. Nutropin Depot administration once or twice per month provides serum levels of GH and IGF-I expected to promote growth, without accumulation of GH, IGF-I, or IGF binding protein-3, in children with GHD.

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.

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.

Objective: To compare the relative utility of GH secretion via pharmacological stimulation, overnight serial sampling, IGF-I levels and auxological variables as predictors of change in height standard deviation score (deltaHt SDS) during GH treatment., Design: A multicentre observational study., Patients: Prepubertal children (n = 825) with idiopathic growth failure who were subsequently treated with GH were divided into two groups, based on their maximum GH response to pharmacological stimulation testing: (1) idiopathic GH deficiency (IGHD), defined by a maximum GH response < 10 microg/l (n = 300); and (2) idiopathic short stature (ISS), with a maximum GH response > or = 10 microg/l (n = 525) (GH conversion factor: 3 IU = 1 mg)., Measurements: Overnight spontaneous GH secretion was measured in all patients. The following characteristics of spontaneous GH secretion were studied: maximum or peak GH, mean peak GH, number of GH peaks, pooled GH, mean GH, and approximate entropy of GH secretion., Results: Although children with IGHD had lower indices of spontaneous GH secretion, there were no differences between IGHD and ISS groups in baseline Ht SDS, growth rate or IGF-I level. The dose and duration of GH therapy were similar. There was no statistically significant difference in the mean (+/- SD) change in Ht SDS (deltaHt SDS) in the two groups (IGHD 1.3 +/- 0.9 and ISS 1.2 +/- 0.8). Measures of spontaneous secretion, such as peak GH, mean of GH peaks, mean area under GH peaks, and mean GH, as well as IGF-I concentrations, were all statistically significantly correlated with deltaHt SDS in IGHD children (P < 0.0001). A significant correlation was also observed for pooled GH (P = 0.002) and approximate entropy (P = 0.01). Children with the most severe ISS (Ht SDS < -3.33) demonstrated a more disorganized pattern of GH secretion compared to children who were not as short (Ht SDS -2.33 to -1.64), as indicated by a higher approximate entropy (0.673 +/- 0.193 vs. 0.607 +/- 0.161, P < 0.004). This increased disorder in GH secretion was accompanied by lower IGF-I levels (104 +/- 99 microg/l vs. 137 +/- 74 microg/l, P < 0.001), even though pooled GH concentrations were indistinguishable between the two groups (2.2 +/- 1.3 microg/l vs. 2.0 +/- 1.0 microg/l). Children with IGHD demonstrated lower approximate entropy than did those with ISS (0.551 +/- 0.235 vs. 0.631 +/- 0.182, P < 0.0001). Duration of GH treatment, height deficit and genetic potential (midparental Ht SDS) were the most important variables influencing deltaHt SDS in children receiving GH therapy. Maximum stimulated GH, IGF-I and indices of spontaneous GH secretion also correlated with deltaHt SDS, but their relative importance varied among diagnostic groups., Conclusions: Patients with GH deficiency demonstrate a reduced capacity for GH secretion, while those with idiopathic short stature exhibit a more disorderly and less functional secretory pattern. Although effective in predicting a response to GH treatment in patients with severe GH deficiency, overnight serial sampling is less practical than other methods currently available. In addition, serial sampling was less useful as a predictor of growth response to exogenous GH in patients with idiopathic short stature.

A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14-17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14-17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.

Background: Nutropin Depots [somatropin (rDNA origin) for injectable suspension] is a long-acting form of human growth hormone (GH) to be administered by subcutaneous (s.c.) injection. The availability of this formulation offers the opportunity for greater convenience and compliance by decreasing the number of injections and frequency of administration required., Objective: To determine the efficacy and safety of a long-acting formulation of GH administered in children with GH deficiency (GHD) once or twice monthly for 2 years., Patients: Fifty-six previously untreated, prepubertal children with GHD received Nutropin Depot 1.5 mg/kg once monthly (1x/mo), or 0.75 mg/kg twice monthly (2x/mo) for 24 months. The mean pretreatment growth rate was 5.0 +/- 2.4 cm/yr., Results: The 0-12 mo growth rate (mean +/- SD) was 8.3 +/- 1.5 cm/yr in the 1x/mo group and 8.2 +/- 2.0 cm/yr in the 2x/mo group. The 12-24 month growth rate was 7.2 +/- 1.5 cm/yr in the 1x/mo group and 6.9 +/- 1.5 cm/yr in the 2x/mo group. During the 24 months of treatment, height standard deviation score (SDS) increased by 1.0 +/- 0.5 SD in the two groups combined (p <0.0001). The corresponding advancement in bone age was 2.2 +/- 0.7 yr, resulting in a gain in Bayley-Pinneau predicted adult height (PAH) SDS of 0.6 +/- 0.9 SD in the 1x/mo group and 0.6 +/- 1.0 SD in the 2x/mo group. No serious adverse events attributable to the study drug were reported. Injection site reactions were common, but resolved without intervention. Pre-dose fasting and postprandial glucose and insulin levels, as well as hemoglobin A1c levels, were unchanged from baseline values., Conclusions: Treatment with Nutropin Depot is associated with catch-up growth and normal skeletal maturation and is a viable alternative to daily injections of GH in children with GHD.

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.

We analyzed data from 65 children with septo-optic dysplasia (SOD) referred for evaluation and followed in the National Cooperative Growth Study (NCGS) Substudy 8 and from 758 children treated with growth hormone (GH) and followed in the NCGS core study. Compared to other children referred for evaluation of short stature, children with SOD were younger (mean age 3.7 +/- 3.6 vs 8.6 +/- 4.9 years), had less severe short stature (mean +/- SD height SDS -1.80 +/- 1.64 vs -2.17 +/- 0.95), and were more likely to be female (46% F vs 31% M). Children with SOD who received GH were older and shorter than those referred and untreated, but the gender distribution was similar. Other pituitary hormone deficits were reported in untreated patients, including thyroid hormone deficiencies (8%) and adrenocorticotropic hormone (ACTH) deficiency (3%), as compared to 27% and 24%, respectively, in GH-treated children. Data on adult height were available for 71 patients, who showed an average gain in height SDS of 1.17 +/- 1.49. GH therapy was well tolerated in children with SOD.

Because estrogen (E) accelerates skeletal maturation it can decrease final height attainable with GH therapy in girls with Turner's syndrome (TS). Nonetheless, as age-appropriate E administration does have psychobehavioral benefits for such patients, we asked whether E treatment in TS could occur without adverse impact on final adult height if GH therapy were started at an earlier age. Near adult height (NAH) was assessed in 344 girls with TS, who had received both GH and E and were followed in the National Cooperative Growth Study database. The groups were divided into quartiles based on age at initiation of GH (2-10, 10-12, 12-14, and 14-18 yr). The longest total and E-free period of GH treatment occurred in the girls who had started treatment in the youngest quartile (mean age, 8.2 +/- 1.5 (SD) yr); they were also exposed to E at the youngest age (12.7 +/- 1.6 yr). Although the girls in the youngest group received E at an earlier age, they had a significantly greater increase (1.8 +/- 0.8) in Lyon height SD score at NAH over Lyon predicted adult height than those in the oldest GH-treated group (0.8 +/- 0.6), which first received E at 15.9 +/- 1.3 yr. Multiple linear regression equations for gain in Lyon height SD score and in height (cm) showed greater increments with a longer period of E-free GH therapy. All four GH age groups had the same NAH, but the youngest quartile was youngest at NAH and likely still having more growth potential. Comparable data were found in 127 TS girls with spontaneous puberty. In conclusion, girls with TS starting GH at an early age have a greater gain in Lyon SD score at NAH compared with those starting later, even though they received E at a younger age. If GH therapy were started early, E treatment could be initiated at a younger, more age-appropriate time without compromising adult height.

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.

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.

We describe 19 males with Aarskog syndrome who were treated with growth hormone (GH) and enrolled in the National Cooperative Growth Study (NCGS). There was a significant increase in both growth rate (3.9 +/- 1.9 cm/yr vs 8.9 +/- 1.7 cm/yr, p < 0.001) and height SD score (change in HtSDS = 1.0 +/- 0.8). The increase in HtSDS was dependent on treatment duration, frequency of injections, weight-for-height SDS, and HtSDS at enrollment. The results of our study suggest a positive effect of GH treatment on growth and adult height in Aarskog syndrome patients.

Several previous investigations have suggested that there may be different growth hormone isoforms in patients with acromegaly. We used three different site-specific monoclonal antibodies (MAbs) to investigate growth hormone (GH) isoforms in serum from an 8 year-old girl with a GH and prolactin secreting adenoma. The pattern of GH-immunoreactivity was dependent on the circumstances of collection. Serum obtained after oral glucose had very little cross reactivity with MAb 352 although concentrations of up to 15 micrograms/l were found with two other MAbs, 033 and 665. MAb 352 does not recognize the 20,000 dalton isoform of GH (20K) while both MAb 033 and 665 do. The same pattern of GH immunoreactivity (low MAb 352, equal and higher MAb 033 and 665) was seen in other baseline samples. In contrast, samples obtained after TRH/GnRH showed immunoreactivity patterns expected for a mixture of 22,000 dalton isoform of GH (22K) with only a small amount of 20K. GH samples obtained during sleep showed both patterns with episodic peaks with equal immunoreactivity superimposed on the basal pattern (decreased activity with MAb 352). Affinity chromatography of basal samples showed that a portion of the GH immunoreactivity was neither 22K nor 20K, although in stimulated samples, over 70% of GH was 22K or 20K GH. In conclusion, the nature of GH isoforms present in serum varies with GH concentration. These differences may contribute to the known difficulty in correlating disease activity and random GH measurements in patients with GH secreting adenomas.

An association between treatment with growth hormone (GH) and the development of leukemia was described in 1988. This perceived association is best explained by the fact that there are more children with GH deficiency (GHD) with risk factors predisposing them to leukemia than in the general population. These factors include previous cancers and their treatment, as well as co-existing conditions such as Down, Bloom and Fanconi syndromes. Examination of large databases of GH-treated individuals shows that GH-treated patients without these risk factors do not have an increased incidence of leukemia.

We used the Genentech National Cooperative Growth Study database to examine differences in weight relative to height (weight for height standard deviation score or WTHTZ) in 3460 patients at enrollment and after one year of therapy with recombinant human growth hormone (rhGH), and in a subset of 450 patients treated for three years with rhGH. The major diagnostic categories were idiopathic growth hormone deficiency (IGHD), organic GH deficiency (OGHD), and idiopathic short stature (ISS). Children with IGHD and ISS were underweight for height at baseline but had a progressive increase in WTHTZ during three years of rhGH therapy. The same pattern applied to children with IGHD associated with septo-optic dysplasia and CNS trauma or infection. However, children with OGHD associated with craniopharyngiomas, other CNS tumors, leukemia, or CNS irradiation were overweight when starting rhGH and showed a decrease in WTHTZ during the first year of rhGH therapy. The increase in WTHTZ during rhGH treatment in children with ISS and OGHD suggests that the GH-induced increase in muscle mass exceeded loss of fat mass. Because children with neoplasm-related OGHD were overweight at baseline, the decline in WTHTZ during the first year of rhGH therapy suggests that loss of fat mass is the predominant effect in this subgroup.

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.

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.

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.

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.

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.

Growth hormone prepared by recombinant DNA technology (somatropin) has been commercially available for over 11 years. More than 38,000 children have been treated with different growth hormone products. While the best response to treatment occurs in children with severe growth hormone deficiency, therapy with growth hormone will increase the rate of statural growth in children with short stature of many different aetiologies. There are few studies of the effect of growth hormone treatment of final adult height, and the magnitude of this effect is harder to gauge, particularly in children with idiopathic short stature. Other benefits of growth hormone treatment in children include improvement in psychosocial functioning and physiological parameters, such as bone mineral density. Adverse effects associated with growth hormone treatment have been relatively uncommon. Most of the safety data on growth hormone have come from large postmarketing databases maintained by 2 pharmaceutical companies. The adverse event profile reported in children treated with growth hormone is different from that found in adults. Peripheral oedema and carpal tunnel syndrome, which are common in adults treated with growth hormone and frequently result in treatment discontinuation, are rare in children. Intracranial hypertension is rare, but can occur in children with growth hormone deficiency, Ullrich-Turner syndrome or renal insufficiency during the first 8 to 12 weeks after the start of growth hormone treatment; it has seldom been reported in adults with growth hormone deficiency. Children with growth hormone deficiency, Ullrich-Turner syndrome or renal insufficiency are prone to develop slipped capital femoral epiphyses both before and during growth hormone treatment. Therefore, limping and complaints of hip or knee pain should be carefully investigated.

National Cooperative Growth Study (NCGS) substudy VIII was designed to determine the characteristics of children who are referred to pediatric endocrinologists for evaluation of short stature but are not treated with growth hormone (GH). No specific course of treatment is required to enter the study. Data on the subjects' characteristics at enrollment, the diagnostic procedures used by the investigators, and the occurrences of various medical conditions and intercurrent illnesses will be collected prospectively and will be compared with the corresponding data on children in the NCGS who are treated with GH.

Background: Data have suggested that any increased incidence of leukemia in growth-hormone (GH)-treated patients was limited to those with known risk factors for leukemia. However, previous studies may have overestimated the numbers of patient-years of risk by not excluding data from "positive-risk-factor" patients. This risk was reanalyzed by using data on children in the National Cooperative Growth Study (NCGS), with correction for this possible confounding factor., Methods: The risk of leukemia in GH-treated patients without known risk factors was determined by using patient-years of GH therapy and patient-years since first exposure to GH therapy and the values obtained were compared with values from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute., Results: Three cases of leukemia in patients without known risk factors were found in the NCGS database; 3.42 cases would be expected in the 119,846 patient-years in the analysis using time since GH exposure. Two of these cases of leukemia occurred during GH therapy (67,773 patient-years); 2.13 cases would be expected., Conclusion: Excluding data on patients with known risk factors for leukemia provides a more accurate estimate of the risks in GH-treated patients. The incidence of leukemia in these patients is comparable to that in the general population of age-matched children.

Growth retardation in children with endstage renal disease (ESRD) is associated with normal to slightly low concentrations of insulin-like growth factor (IGF)-I and increased concentrations of IGF-binding proteins (IGFBPs) in serum. Consequently, IGF-I bioactivity is reduced in serum from uremic patients presumably due to a decrease in the concentration of free IGF-I. Improvement of linear growth with growth hormone (GH) treatment of uremic children is thought to be due to increased IGF-I/IGFBP ratio, thus resulting in increased free IGF-I levels during treatment. The purpose of the present study was to determine whether free/dissociable IGF-I levels are in fact low in uremic children and whether increased growth velocity during GH treatment is associated with an increase in the free IGF-I concentration. Serum total and free/dissociable IGF-I concentrations were measured in 5 children with ESRD before and during treatment with GH, and in control children matched for age, pubertal status, and body mass index. Height velocity increased from 3.7 +/- 1.0 cm/yr to 6.5 +/- 1.2 cm/yr with an increment in height SDS at the end of the first year of GH treatment. Free/dissociable IGF-I concentrations tended to be lower in uremic children compared to control children (3.0 +/- 0.3 vs 7.3 +/- 2.1 micrograms/l, respectively). During GH treatment, free/dissociable IGF-I levels increased significantly to 8.5 +/- 1.0 micrograms/l at 3 months and 6.9 +/- 1.4 micrograms/l at 6-24 months, p < 0.05 compared to pretreatment. Total IGF-I levels were 243 +/- 18 micrograms/l in children with ESRD before treatment and these values also increased during GH treatment (740 +/- 114 micrograms/l at 3 months and 442 +/- 44 micrograms/l at 6-24 months, p < 0.05, compared to pretreatment). Total IGF-I concentration in the control group was 439 +/- 114 micrograms/l. These results support the hypothesis that growth retardation in children with chronic renal failure is associated with a reduction in the concentration of free, biologically available IGF-I, and that increased growth velocity during GH treatment of these children is associated with restoration of free IGF-I concentrations.

Near-adult height (AH) was determined in 121 children (72 males and 49 females) with GH deficiency (GHD) who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as a SD score was -0.7 +/- 1.2 (mean +/- SD), significantly greater than the pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score (-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 +/- 1.3). In contrast to studies of GH treatment outcome, which used pituitary-derived GH (pit-GH) in lower doses, we found that males did not have a higher AH SD score than females, spontaneous puberty did not diminish AH, and AH was significantly greater than that predicted at the start of GH treatment. In a multiple regression equation, the statistically significant variables (all P < 0.0001) related to AH (r2 = 0.70) were the following: duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH) and height at the start of GH, and growth rate during first year of GH. For the AH SD score (r2 = 0.47), pretreatment predicted AH, duration of GH, and bone age delay were significant (P < 0.0002) explanatory variables. Bone age delay (chronological age-bone age) had a negative impact on the AH SD score. Target height, etiology of GHD, previous treatment with pituitary GH, and the presence or absence of spontaneous puberty did not significantly improve the prediction of AH. Early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.

A small portion of circulating insulin-like growth factor I (IGF-I) is detected in the free or readily dissociable state, which is thought to be the metabolically active form. The amount of free/dissociable IGF-I in serum is dependent on a complex interplay between the production rate and the concentrations of IGF-I and IGF-binding proteins (IGFBPs). IGF availability is also influenced by posttranslational changes in IGFBPs that affect the affinity of IGFBPs for IGF-I. In the present study, we examined whether a short term fast (approximately 12 h) alters the serum concentration of free/dissociable IGF-I, and whether these changes are associated with alterations in IGFBP-1 and the proteolysis status of IGFBP-3. Circulating free/dissociable IGF-I concentrations, as assessed by a two-site immunoradiometric assay, did not differ between fasting and 4 h after a morning meal (1.48 +/- 0.07 vs. 1.50 +/- 0.07 microgram/L, respectively). Likewise, free/dissociable IGF-I levels measured by RIA after separation by centrifugal ultrafiltration were not different between the two groups (1.43 +/- 0.14 vs. 1.38 +/- 0.18 microgram/L, respectively). IGF-I bioactivity, as measured by thymidine incorporation by fibroblasts, did not differ in fasting and 4-h postprandial sera. There was no difference in IGFBP-3 and total acid-ethanol-extractable IGF-I concentrations in serum from fasted and fed subjects. In contrast, the concentration of IGFBP-1 in the serum was increased approximately 5-fold in the fasted state compared to fed values. IGFBP-1 existed in a highly phosphorylated form under fasting conditions. There was no change in IGFBP-3 proteolysis assessed either in vivo or in vitro between the fasting and fed states. The results indicate that a physiologically relevant short term overnight fast does not alter the circulating levels of free/dissociable IGF-I despite a marked elevation in IGFBP-1.

We measured human chorionic gonadotropin (hCG) in cord sera of 22 infants born to women infected with the human immunodeficiency virus-1 (HIV-1). hCG was also determined in cord sera from 173 infants born at a suburban hospital to HIV-1-seronegative women. The findings indicate that 16 (9%) of 173 HIV-1-seronegative samples had hCG levels greater than 90 IU/L (values were distributed as a Poisson curve). In contrast, 8 (36%) of the 22 infants born to HIV-1-infected women had hCG levels in excess of 90 IU/L, and 7 (88%) of these were shown to be HIV-infected. The remaining 14 infants born to HIV-1-infected women had low hCG levels, and 3 (21%) of the 14 had HIV infection. Mean follow-up time for HIV-uninfected infants was 17.5 months (range 9 months to 3 years). A statistically significant association between maternal-fetal HIV-1 transmission and hCG levels > or = 90 IU/L in cord sera was observed (p = 0.02). The difference between CD4 counts among mothers who transmitted HIV and those who did not was also statistically significant (p = 0.025). On the basis of this study's findings, we propose that cord blood hCG may serve as a surrogate marker for HIV-1 infection. Testing hCG levels in cord sera is an inexpensive and readily available screening test for early identification of infants at increased risk for getting HIV-1 from their mothers.

Objective: We have recently demonstrated multiple aberrations in the GH-IGF axis in the sera of children with untreated insulin-dependent diabetes mellitus (IDDM) which were restored after insulin replacement. However, the net result of these alterations in the IGF system on the concentrations of free/biologically available IGF-I in the serum have not been examined directly in diabetic children. In the present study, the effect of diabetes and subsequent insulin replacement on the circulating free IGF-I concentrations are assessed., Design: Fasting venous serum samples were obtained longitudinally, before and at various times after the initiation of insulin treatment in untreated diabetic subjects., Subjects: Ten prepubertal, aged (mean +/- SEM) 6.3 +/- 1.0 years, and six adolescent, aged 12.7 +/- 1.1 years, subjects with newly diagnosed and untreated IDDM, and age and pubertal status-matched control children and adolescents were recruited., Methods: The serum samples were collected before initiating insulin treatment and 12-24 h, 1 week, and 1 month thereafter in subjects with IDDM. Insulin doses ranged from 0.5 to 1.2 U/kg/day., Measurements: Free IGF-I concentration was assayed by a recently developed two-site immunoradiometric assay. Total IGF-I was measured by radioimmunoassay after acid-ethanol extraction of binding proteins. Differences in free and total IGF-I concentrations in IDDM subjects before and during insulin treatment were analysed by repeated measures analysis of variance followed by pairwise multiple comparisons test. In seven subjects with IDDM, where serum IGFBP-1 and IGFBP-3 concentrations, and IGFBP-3 protease activity had also been measured in a previous study, the relationship between these variables and circulating free IGF-I concentrations were examined by linear regression analysis., Results: Free IGF-I concentrations in prepubertal subjects with IDDM were 0.9 +/- 0.2, 1.5 +/- 0.3, 1.6 +/- 0.3 and 2.5 +/- 0.4 micrograms/l before, 1 day, 1 week and 1 month after insulin treatment, respectively. Free IGF-I concentrations of control prepubertal children were 2.6 +/- 0.5 micrograms/l. Pubertal subjects had higher free IGF-I concentrations than prepubertal subjects but demonstrated a similar type of pattern; before insulin 2.3 +/- 1.1, 1 day 3.8 +/- 1.3, 1 week 3.7 +/- 0.6, 1 month 6.5 +/- 1.5 vs pubertal controls 7.7 +/- 2.0 micrograms/l. Total IGF-I concentrations were also reduced in untreated diabetic subjects and showed a slower pattern of normalization than free IGF-I concentrations. Free IGF-I concentrations correlated positively with total IGF-I and negatively with IGFBP-1 concentrations. There was no significant correlation between free IGF-I and either serum IGFBP-3 concentrations or IGFBP-3 protease activity., Conclusion: Alterations in the IGF system during untreated IDDM lead to a reduction in circulating free IGF-I concentrations which is restored progressively during insulin treatment. An increase in free IGF-I precedes that of total IGF-I suggesting that the former is a more sensitive indicator of the metabolic status. An inverse correlation between free IGF-I and IGFBP-1 supports the hypothesis that IGFBP-1 plays an important role in the acute modulation of free IGF-I levels.

For the National Cooperative Growth Study II substudy, data on spontaneous growth hormone (GH) secretion were collected from 5106 children with short stature. Of these, 2123 with complete 12-hour samples were subsequently enrolled in the NCGS. Compared with NCGS enrollees who were not in the NCGS II substudy, these children were significantly older (11.3 +/- 3.3 years vs 9.9 +/- 4.2 years), had a higher maximum reported GH level (13.3 +/- 10.5 micrograms/L vs 9.2 +/- 8.7 micrograms/L), and were more likely to be male (71% vs 62%) and pubertal (27.3% vs 21.9%) (p<0.001) for all). Height deficit, bone age delay, and pretreatment growth rates were similar. Children who were classified as having GH deficiency on the basis of their response to standard pharmacologic tests had lower spontaneous GH secretion than those who were classified as having idiopathic short stature, but considerable overlap was seen between the two groups on all indexes of spontaneous GH secretion. This finding suggests that the investigators were using serial sampling studies in examining children with short stature who were not growing well but had "normal" GH responses to standard pharmacologic testing.

Objective: Little information is available regarding the regulation of serum acid-labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin-like growth factor (IGF) ternary complex in children with untreated insulin-dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients., Design: Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate-rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1-week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH., Patients: Twenty children and adolescents with untreated IDDM, aged 1.2-16 years, and 6 young adult patients with severe burns aged 17-28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults., Measurements: Serum insulin, GH, cortisol and IGF-I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods., Results: Serum ALS levels were lower in untreated children with IDDM (69 +/- 6% of control children). Insulin therapy significantly increased serum ALS (79 +/- 5%, P < 0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 +/- 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 +/- 15% of control values (P < 0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 +/- 27%). Serum IGF-I concentrations increased nearly 2.5-fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera., Conclusion: Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF-I concentrations in both conditions, suggesting that IGF-I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS levels in catabolic states and helps to restore the IGF system.

We evaluated the response to growth hormone (GH) therapy in 150 children (97 boys) with Noonan syndrome (NS) by analyzing growth data from children with NS who were enrolled in the National Cooperative Growth Study and compared those data with National Cooperative Growth Study growth data from children with idiopathic growth hormone deficiency (IGHD) and Turner syndrome (TS). Children with NS were significantly shorter than those with IGHD and TS. The annualized growth rates for years 1, 2, 3, and 4 of therapy in patients with NS who were naive to previous GH therapy were significantly greater than baseline. Their growth rates for years 1, 2, 3, and 4 were intermediate between those in children with IGHD and TS and were significantly different from both. A significant improvement occurred in height SD scores for those 42 children with NS who have been monitored for at least 4 years of GH therapy. Three of six boys with NS for whom adult height data were available exceeded their pretreatment predicted heights.

The National Cooperative Growth Study has monitored the safety of recombinant human GH (rhGH) since 1985. Data have been collected from more than 19,000 children representing over 47,000 patient-years of rhGH treatment. Children receiving GH for renal disease were more likely to develop problems such as intracranial hypertension than those with GH deficiency (P < 0.01). Children with idiopathic short stature were less likely to develop slipped capital femoral epiphysis than those with GH deficiency or Turner's syndrome (P < 0.01). There was no evidence of an increased recurrence of leukemia or central nervous system tumors. There were 3 new cases of leukemia in children without known risk factors for developing leukemia and 5 cases in children with known risk factors. Growth deceleration associated with high affinity, high capacity antibodies to GH was found in only 2 of 5039 subjects tested (0.04%). Major adverse events in association with rhGH treatment have been rare, and preexisting medical conditions such as renal insufficiency may affect their frequency.

We examined the association between slipped capital femoral epiphysis (SCFE) and growth hormone (GH) treatment in 16,514 children who had not been treated with GH prior to their enrollment in the National Cooperative Growth Study. Fifteen children had SCFE prior to receiving GH therapy, 26 developed SCFE during GH treatment, and one had SCFE on one side prior to GH treatment and developed it on the contralateral side while receiving GH. Children with GH deficiency were significantly more likely to develop SCFE while on GH treatment than were children with idiopathic short stature (p = 0.006). There was no difference between GH-deficient girls and boys in the risk of developing SCFE during GH treatment. There were 3 cases of SCFE in girls with Turner syndrome before GH treatment and 3 during. Typically, children who developed SCFE while on GH were older, heavier, and grew more slowly during the first year of GH than those who did not. Children with GH deficiency, Turner syndrome, and other known causes of short stature are more likely to develop SCFE before or during GH treatment than children with idiopathic short stature.

Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with female external genitalia. Such individuals are usually raised as females, but virilize at the time of expected puberty as the result of increases in serum testosterone. Here we describe mutations in 12 additional subjects/families with this disorder. The 14 mutations characterized to date include 10 missense mutations, 3 splice junction abnormalities, and 1 small deletion that results in a frame shift. Three of these mutations have occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations have been constructed and expressed in reporter cells; 8 of the 9 missense mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function, missense mutations testosterone levels in testicular venous blood were very low. Considered together, these findings strongly suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.

The regulation of circulating insulin-like growth factor-binding protein-2 (IGFBP-2) in humans is not well understood. In vitro and animal data have identified the role of insulin in the regulation of IGFBP-2, but such a relationship has not been established clearly in humans. In the present study, serum IGFBP-2 concentrations were assessed by Western ligand blot and immunoblot analysis in children with newly diagnosed and untreated insulin-dependent diabetes mellitus (IDDM) and maturity-onset diabetes of the young before and at various times after insulin therapy. For comparison, IGFBP-2 levels were also determined in lean and obese age-matched controls. Children with IDDM were grouped according to their serum bicarbonate levels at the time of presentation (group A, > 20; group B, 13-20; group C, < 13 milliequivalents/L). Densitometric analysis demonstrated that before insulin therapy, group A patients had serum IGFBP-2 levels comparable to those in lean controls, and no significant change in IGFBP-2 was observed during insulin therapy. However, group B patients had a 2-fold elevation in IGFBP-2 levels before insulin therapy compared to lean controls. In these patients, IGFBP-2 tended to decrease at 1 week, but was not significantly reduced until 1 month after the initiation of insulin therapy. Group C patients had a 2.5-fold elevation of IGFBP-2 before treatment, which normalized by 1 month after treatment. Children with maturity-onset diabetes of the young, who had insulin levels and body mass indexes greater than IDDM patients and lean controls, had significantly lower IGFBP-2 levels than both lean and obese controls. IGFBP-2 levels tended to decrease further during insulin therapy. These results indicate that long standing alterations in serum insulin concentrations beyond the physiological range have significant influence on serum IGFBP-2 levels in children and confirm earlier findings that serum IGFBP-2 levels are not acutely regulated by insulin.

The introduction of human growth hormone (GH) prepared by recombinant DNA technology has resulted in increased numbers of children and adults receiving treatment. This trend has led to questions concerning the safety of GH, particularly when used for indications other than GH deficiency. This review discusses the effects of GH on fluid, lipid, and carbohydrate metabolism; the risk of intracranial hypertension or pseudotumor cerebri; the effects on the skeletal system; the risk of malignancy; and the effects on the immune system. At present, GH treatment appears to be safe, although long-term follow-up of GH-treated patients is necessary.

Limited proteolysis of serum insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been described in various conditions and may increase the bioavailability of IGFs. The physiological regulators of serum IGFBP-3 protease activity are unknown. To characterize the relationship between insulin and IGFBP-3 protease activity, we have examined serum IGFBP-3 proteolysis in children with untreated insulin-dependent diabetes mellitus (IDDM) and have followed the effect of insulin therapy on serum IGFBP-3 proteolysis at 1 day, 1 week, and 1 month after the initiation of insulin therapy. Ligand blot analysis of sera from untreated children with IDDM showed that intact IGFBP-3 was 50 +/- 9% of the age-matched control pool. After the initiation of insulin treatment, IGFBP-3 did not change significantly at 1 day after treatment but increased dramatically at 1 week (90 +/- 13%) and 1 month after treatment (102 +/- 13%). In contrast, when measured by immunoradiometric assay (which detects both intact and fragments of IGFBP-3), IGFBP-3 levels were 70% of the control pool before insulin therapy and did not increase significantly until 1 month after treatment. Immunoblot analysis demonstrated that intact IGFBP-3 doublet was diminished to 41 +/- 7% of controls, whereas the major IGFBP-3 fragment (30 kDa) was increased in IDDM sera before insulin therapy. After insulin, intact IGFBP-3 increased and the 30-kDa fragment decreased to values comparable to those observed in controls. In vivo IGFBP-3 proteolysis, which implies preassay exposure of serum IGFBP-3 to proteases, was estimated by immunoblot analysis. IGFBP-3 proteolysis was increased before insulin therapy (160 +/- 9%) and decreased to 81 +/- 9% at 1 week and to 71 +/- 11% at 1 month after insulin treatment. Residual serum IGFBP-3 protease activity was estimated by a 125I-IGFBP-3 degradation assay. Serum IGFBP-3 protease activity increased significantly in untreated diabetics, compared with activity in controls (128 +/- 5% vs. 99 +/- 11%). During insulin therapy, serum IGFBP-3 protease activity decreased gradually to 91 +/- 5% of control values at 1 month. Molecular sizes of the IGFBP-3 proteolytic fragments (30 kDa, 24 kDa, and 19 kDa) and inhibition profile of IGFBP-3 protease were similar in IDDM and pregnancy sera, indicating that similar proteases (cation-dependent serine proteases) were active in both conditions. These results suggest an important role of insulin in the regulation of IGFBP-3 protease activity. Increased IGFBP-3 proteolysis in the sera of children with IDDM may serve to counteract the catabolic state induced by insulin deficiency.

To further characterize the mechanism of impaired growth in children with insulin-dependent diabetes mellitus, we examined the serum components of the insulin-like growth factor (IGF) system in 11 children with new-onset insulin-dependent diabetes mellitus and followed the effect of insulinization on the IGF system longitudinally 1 day, 1 week, and 1 month after starting insulin treatment. Before insulin therapy, serum IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), and GH-binding protein (GHBP) levels were significantly decreased, whereas IGFBP-1 and cortisol were significantly increased in diabetic children compared to those in an age-, sex-, and stage of puberty-matched control group. Random serum GH concentrations did not differ significantly. The alterations in the IGF system reversed with insulin therapy in a sequential manner. IGFBP-1 fell rapidly and was comparable to control values within 24 h after insulin treatment. IGF-I rose 1 week after treatment, reaching levels comparable to those in controls and continued to rise through 1 month of treatment. IGF-II, IGFBP-3, and GHBP showed a slower pattern of change, with their levels reaching control values only 1 month after the start of insulin treatment. Improvement in glycemic control, as determined by a change in hemoglobin-A1c, correlated positively with improvement in IGF-I, IGF-II, IGFBP-3, GHBP, and weight gain after 1 month of insulin therapy. These data are consistent with the hypothesis that changes in the IGF system in the insulinopenic state are similar to those during nutritional deprivation and may serve to minimize IGF's anabolic actions. The decreases in IGF-I, IGF-II, and IGFBP-3 may in part be due to a decrease in the GHBP/receptor. However, the observation that an increase in serum IGF-I was observed earlier than an increase in GHBP and without a significant change in serum GH suggests a direct stimulatory effect of insulin on liver IGF-I production or reversal by insulin of some postreceptor defect in GH action independent of GHBP.

Steatorrhea is seen in 18-24% of patients with autoimmune polyglandular disease (APD) type 1. The etiology and pathophysiology of the steatorrhea in this disease are unknown. We present a patient with APD type 1 and steatorrhea in whom biopsies revealed intestinal lymphangiectasia. This association has not been previously described. Intestinal lymphangiectasia may explain the steatorrhea in some patients with ADP type 1. As blind intestinal biopsies may miss areas of intestinal lymphangiectasia, endoscopically directed intestinal biopsies should be included in the evaluation of steatorrhea in APD type 1.

We measured T4, T3, TSH, and TBG in 53 children (both asymptomatic and symptomatic) with human immunodeficiency virus (HIV) antibodies, and 17 controls. Although most had normal T3 and T4 levels, two children with acquired immuno-deficiency syndrome (AIDS), who were very ill when studied, had low T3 values. TBG and TSH levels were higher in children with AIDS than in other HIV-infected children or controls (P < 0.005). Increased TSH levels were found in 5 children with AIDS who were recovering from severe illnesses. TSH levels returned to normal without treatment. In summary: 1) the pattern of thyroid abnormalities in children with AIDS was different from that seen in healthy controls, critically ill children, other HIV-infected children, and HIV-infected adults; 2) if an increased TSH is found, measurement should be repeated before instituting thyroxine therapy; 3) an increased TBG is not seen in HIV-infected children until clinically evident AIDS is present.

To evaluate the presence of different GH isoforms in serum of girls with Turner's syndrome, we measured the serum GH content using RIAs with three different site-specific monoclonal antibodies (MAbs). We compared the results to those obtained with authentic GH and GH isoforms. Compared to pituitary GH (mol wt, 22K daltons) as the standard for all three MAbs, serum from girls with Turner's syndrome did not displace tracer [125I]GH equally with all three MAbs. The relative amounts of GH-immunoreactive material found in Turner's syndrome were different from the amounts observed in normal adults and most children with idiopathic short stature. The presence of GH, other than 22K GH, in serum from girls with Turner's syndrome was confirmed by affinity chromatography. The existence of different isoforms of GH, as shown by different cross-reactivity patterns with different MAbs to GH, may explain the conflicting results reported for GH secretion in girls with Turner's syndrome.