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OBJECTIVE: To study whether body mass index (BMI) is different in girls with Turner syndrome (TS) compared to normal girls, and whether BMI in TS is affected by growth hormone (GH) treatment. DESIGN: A retrospective cross-sectional study. SUBJECTS: 2468 girls with TS enrolled in the National Cooperative Group Study (NCGS), a collaborative surveillance study for assessing GH-treated children. MEASUREMENTS: BMI and BMI standard deviation score (BMI SDS) at baseline and during GH treatment were computed from height and weight data. RESULTS: BMI in TS patients increases with age as expected. However, BMI SDS increased starting at about age 9 y. A similar pattern of increase in BMI SDS was observed after each year of GH treatment for up to 4 y, but GH treatment did not change the magnitude of increase. BMI and BMI SDS curves before and during GH treatment were essentially superimposable. CONCLUSION: These findings suggest that mechanisms specific for TS are responsible for the age-related increase in BMI SDS. This increase was unaffected by GH treatment. [ABSTRACT FROM AUTHOR]

Proton relaxation rate studies have been used to study the interaction between arginine kinase from two sources, Homarus vulgaris and Homarus americanus, and manganous ion, MnADP- and MnATP2+, respectively. There was negligible interaction between Mn2+ and the H. vulgaris enzyme but a small effect with the H. americanus enzyme. In both cases, a large enhancement of the proton relaxation rate was seen on the addition of ADP or ATP to a solution containing Mn2+ and enzyme. It was concluded that the enzyme combines with MnADP- or MnATP2- rather than with Mn2+. Enhancements of the proton relaxation rate of the ternary complexes, MnADP-E (45), Mn2'-dADP-E (28) and MnATP-E (17), were obtained with the H. vulgaris arginine kinase and Mn3'-dADP- and Mn2'-dATP2- were also demonstrated to form ternary complexes with this enzyme. For arginine kinase from H. americanus, values for MnADP-E (17), Mn2'-dADP-E (approx. 12) and MnATP-E (approx. 8) were determined. A comparative kinetic study demonstrated reasonable agreement between the kinetically determined Km values and dissociation constants from the proton relaxation rate data. It was also found that for both enzymes, there was a correlation between the enhancement and maximum velocity values, ADP > 2'-dADP and ATP > 2~-dATP which could be interpreted as indicative of a graded degree of substrate induced conformational change. The proton relaxation rate and kinetic studies indicated small but probably significant differences in the properties of the two enzymes. Proton relaxation rate studies provided evidence fora second substrate induced conformational change on the addition of L-arginine to the ternary MnADP-enzyme complex. No significant effect was observed with D-arginine, which is a competitive inhibitor with respect to L-arginine. [ABSTRACT FROM AUTHOR]

Growth failure associated with severe primary insulin-like growth factor 1 (IGF-1) deficiency (SPIGFD), a condition defined as basal IGF-1 standard deviation score (SDS) less than or equal to -3 and height SDS less than or equal to -3 in a child with normal or elevated levels of growth hormone, can be successfully treated with the recombinant human IGF-1 mecasermin. In this review, we describe the most safe and effective way to use mecasermin in the treatment of patients with SPIGFD, including how to initiate dosing, key side effects, and how to monitor treatment. Finally, mention of how to reinitiate therapy is made, given the recent drug shortage with mecasermin.

Surgical resection is often not curative in patients with acromegaly and long-acting somatostatin analogues (lanreotide or octreotide) are often needed. This study assessed the efficacy and safety of self- or partner-administration of lanreotide in patients with acromegaly. This was a six-month, single-arm, open-label study conducted at 13 endocrinology clinics. Fifty-nine patients received deep subcutaneous lanreotide injections every 28 days. Twelve patients started on 120 mg lanreotide and forty-seven started on 90 mg lanreotide. At week 16, the dose was adjusted to 60, 90 or 120 mg based on insulin-like growth factor-1 (IGF-1) levels at week 12. Fifty-nine patients with acromegaly either switched from long-acting octreotide (switch; n = 33) or were somatostatin analogue treatment-naïve or not currently taking long-acting octreotide ("other"; n = 26). The key endpoints included the percentage of patients/partners able to self- or partner-inject lanreotide and those with normal IGF-1 or growth hormone (GH) levels at week 24/early termination. 100% of patients/partners correctly self- (n = 41) or partner-injected (n = 18) lanreotide by week 4. By week 24/early termination, IGF-1 levels were controlled in 93.7% of switch and 46.2% of "other" patients, while GH levels were controlled in 76.9% and 39.1% of patients, respectively. Both IGF-1 and GH were controlled in 73.1% of switch and 30.4% of "other" patients. Most switch patients (81%) reported they preferred lanreotide over long-acting octreotide for future use (P = 0.0001). Self- or partner-administration of lanreotide is generally well tolerated and associated with IGF-1 and GH control in many lanreotide-naïve patients with acromegaly.

Extensive resection of the intestinal tract frequently results in inadequate digestion and/or absorption of nutrients, a condition known as short bowel syndrome (SBS). Several therapies, including parenteral nutrition (PN), bowel rehabilitation, and surgical procedures to reconstruct the bowel, have been used for patients with SBS. However, these treatments only partially correct the underlying problem of reduced bowel function in some patients. This review investigates the results of studies of recombinant human growth hormone (r-hGH) in patients with SBS. In one randomized, controlled and five open-label studies, treatment with r-hGH significantly increased absorption of energy, protein and/or carbohydrates. Four studies also demonstrated significantly increased body weight, lean body mass, total body potassium and/or total body water in response to r-hGH. However, in two other randomized controlled trials, r-hGH had no significant effect on energy or fluid absorption. In one randomized, controlled study and six open-label trials, treatment with r-hGH also allowed a majority of patients, including those with no colon and significant bowel resection, to eliminate or substantially reduce PN. Optimal clinical benefits appear to be achieved when r-hGH is administered in combination with a specialized oral diet and perhaps with glutamine. Although the use of r-hGH to treat SBS patients remains controversial, results from these studies suggest that short-term r-hGH treatment in combination with optimized medical and dietetic treatments can enhance bowel absorption and function and, with the continuation of optimized medical and dietetic treatments, may reduce PN requirements for a wide range of patients with SBS.

Given the lack of published guidelines regarding the use of trophic factors to treat patients with short bowel syndrome (SBS), a group of experts in the field convened to discuss best-practice strategies. Trophic factors, such as recombinant human growth hormone (r-hGH) and glucagon-like peptide-2 (GLP-2), may enhance intestinal adaptation and decrease parenteral nutrition (PN) requirements; therefore, their utility in treating SBS patients was evaluated. Available clinical data on use of r-hGH therapy in SBS patients were discussed, as were the utility of r-hGH in the PN weaning process, the optimal timing of r-hGH therapy, and how to select appropriate patients for r-hGH therapy. In addition, contraindications and precautions as well as adverse effects of r-hGH treatment were discussed. The meeting culminated with the development of a treatment algorithm to summarize best-practice recommendations for the management of SBS in adult patients. This algorithm involves attempting to wean patients off PN without the use of trophic factors. If this is unsuccessful, it is recommended that patients be treated with an r-hGH regimen or participate in investigational studies using other trophic factors.

To determine the effect of method of growth hormone (GH) administration on patient outcomes, we studied data from the GHMonitor, an electronic database registry of North American children treated with Saizen GH (somatropin [rDNA origin] for injection). Data from 631 children, 305 treated with needle and syringe and 326 treated with cool.click needle-free device, were analyzed. The groups were balanced for factors known to affect GH treatment response. There was no difference in response to GH over 2 years of treatment whether assessed by growth rate, change in height SD score, or change in height age. Although the majority of patients were compliant with GH therapy (84.6% of needle-free delivery system [NFDS] and 76.3% of needle and syringe patients missed <3 doses per month), significantly more patients using needle and syringe missed over one-half of their prescribed GH dose (13.4% needle and syringe patients versus 6% of NFDS patients, P=.002). In this group of poorly compliant patients, growth rates were significantly lower than in patients who missed fewer doses. Thus in patients where compliance is an issue, use of the NFDS may result in better outcomes.

Objective: Recombinant human growth hormone (rhGH) has been used to improve the growth retardation associated with chronic renal insufficiency (CRI) and end-stage renal disease. We determined the incidence of one of four targeted adverse events (AEs): malignancy, slipped capital femoral epiphysis (SCFE), avascular necrosis (AN), and intracranial hypertension (ICH)., Study Design: During a 6.5-year period, we prospectively assessed patients enrolled in the CRI, dialysis, and transplant registries of the North American Renal Transplant Cooperative Study. The availability of an untreated control population facilitated determining whether or not there was the association between the AE and rhGH treatment., Results: Of the targeted AE, the only significant relation with rhGH treatment was the presence of ICH in patients with CRI; however, in all 3 instances, ICH occurred 2, 50, and 1131 days after discontinuation of rhGH. Considering that the mechanism of ICH in rhGH-treated patients is thought to be increased CSF production, rhGH probably had no role in the development of ICH in at least 2 of the 3 patients with CRI. A number of nontargeted AE were identified that have been associated with rhGH treatment in patients without renal disease. The incidence of glucose intolerance, pancreatitis, progressive deterioration of renal function, acute allograft rejection, and fluid retention were not more frequent in those receiving rhGH treatment compared with the control population., Conclusions: This report validates the importance of a control population in ascribing AE to any therapeutic intervention. Previously identified AE associated with rhGH treatment are infrequent in patients with CRI and end-stage renal disease.

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.

We reviewed adverse event (AE) data in the National Cooperative Growth Study from start-up (1985) until January 1, 1999. Enrollment was 33,161. A total of 2,632 AE reports were received; 863 were serious events, with 156 deaths. The most common cause of death was recurrence of intracranial neoplasm. There were 20 reports of leukemia, and the standard morbidity ratio (SMR) was 0.73 (95% CI: 0.20-1.86) for the four cases without risk factors. There were 35 reports of extracranial nonleukemic malignancy, and the SMR was 0.44 (95% CI: 0.24-0.74) for the 14 cases without risk factors. The recurrence rate for all brain tumors present at baseline was 7.6%, and for craniopharyngiomas, 6.4%. There were 49 reports of intracranial hypertension (20 patients had papilledema), 68 reports of diabetes/hyperglycemia, 45 of slipped capital femoral epiphysis, 136 of scoliosis, and five of pancreatitis. There was no evidence of increased incidence of leukemia or extracranial nonleukemic malignancies among patients without prior risk factors. Intracranial hypertension does not necessarily occur early in growth hormone therapy. Other findings were consistent with past observations.

Objective: To evaluate post-transplant outcomes for patients treated with human growth hormone (rhGH) during the course of chronic renal insufficiency (CRI)., Study Design: Patients (the "cohort" group) were identified who had been enrolled in 2 controlled studies to determine the efficacy and safety of rhGH in growth-retarded children with CRI and were subsequently enrolled in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and received a renal transplant. Patient survival, graft survival, time to first acute rejection episode, causes of graft failure, adverse events, and serial growth data from transplant to 60 months were evaluated. Data from the cohort group of 102 patients were compared with data from 4913 primary transplants from "other NAPRTCS" recipients (the "control" group)., Results: No significant difference was seen in patient survival or graft survival, incidence of acute rejection episode, or time to first rejection episode between the cohort and control groups. No specific adverse events were attributable to previous rhGH treatment. Only 2 patients had post-transplant lymphoproliferative disease in the cohort group, with no other malignancies reported. The mean height z scores in the cohort group at baseline and 60 months after transplant were -1.92 and -1.90, and the Deltaz score at 60 months was +0.20 compared with the control group (-1.88 and -2.10)., Conclusions: Treatment of growth-retarded patients with CRI does not adversely affect graft function after renal transplantation. "Catch-down" growth does not occur after renal transplantation.

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.

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.

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.