Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naïve patients with acromegaly.

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.

An overview of the GHMonitor, a registry of children treated with Saizen somatropin [recombinant hGH for injection].

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.

Patient outcomes in the GHMonitor: the effect of delivery device on compliance and growth.

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.

Septo-optic dysplasia/optic nerve hypoplasia: data from the National Cooperative Growth Study (NCGS).

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.

Neonatal hypoglycemia in a growth hormone registry: incidence and pathogenesis.

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

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

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

A long-acting human growth hormone (Nutropin Depot): efficacy and safety following two years of treatment in children with growth hormone deficiency.

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.

Age of thelarche and menarche in contemporary US females: a cross-sectional analysis.

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.

Managing the child with severe primary insulin-like growth factor-1 deficiency (IGFD): IGFD diagnosis and management.

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.

Treatment of adult short bowel syndrome with recombinant human growth hormone: a review of clinical studies.

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.

Indications and recommendations for the use of recombinant human growth hormone in adult short bowel syndrome patients dependent on parenteral nutrition.

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.

Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease.

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.

Do growth hormone (GH) serial sampling, insulin-like growth factor-I (IGF-I) or auxological measurements have an advantage over GH stimulation testing in predicting the linear growth response to GH therapy?

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.

Screening girls with Turner syndrome: the National Cooperative Growth Study experience.

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