Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort.

CONTEXT: The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. OBJECTIVE: This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. METHODS: Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. RESULTS: The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. CONCLUSION: Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Long-term Safety of Growth Hormone in Adults With Growth Hormone Deficiency: Overview of 15 809 GH-Treated Patients.

CONTEXT: Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. OBJECTIVE: We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. METHODS: The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. RESULTS: A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. CONCLUSION: These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.

OBJECTIVE: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. DESIGN: Global (15 countries), multicentre, non-interventional study (2004-2017). METHODS: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes). RESULTS: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients. CONCLUSION: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

Growth hormone deficiency and central precocious puberty in Klinefelter syndrome: report of a case and review of KIGS database.

Growth hormone deficiency (GHD) and central precocious puberty (CPP) have each, individually, been described in patients with Klinefelter syndrome. However, the combination of GHD, CPP, and Klinefelter syndrome has never been reported. We described a Klinefelter syndrome patient who developed GHD at age 2 10/12 years and CPP at 8 6/12 years. Despite CPP, GnRH agonist therapy was not initiated because of his excellent predicted adult height. At 11 8/12 years, his height was 164.6 cm, close to his mid-parental target height of 165 cm. We report an additional nine patients with Klinefelter syndrome and GHD from the Pfizer International Growth Study (KIGS) database, none of whom had CPP. We conclude that the combination of GHD and CPP is very rare in Klinefelter syndrome and that CPP is unlikely to compromise final adult height.

Unreplaced sex steroid deficiency, corticotropin deficiency, and lower IGF-I are associated with lower bone mineral density in adults with growth hormone deficiency: a KIMS database analysis.

CONTEXT: GH deficiency (GHD) is associated with low bone mineral density (BMD). Risk factors for lower BMD in this GHD population have not been fully elucidated. In particular, there are limited published data in GH-naïve subjects. OBJECTIVE: The objective of the study was to identify endocrine correlates of low BMD in treatment-naïve adult GHD subjects. DESIGN: This was a retrospective analysis of data extracted from the (Pfizer International Metabolic Study) KIMS database. SETTING: The study was an international epidemiological survey of more than 15,000 adult GHD patients from 31 countries. PATIENTS: A total of 1218 subjects with stringently defined GHD of adult onset (641 women and 577 men) who were GH naïve and had BMD measured in the posterior anterior lumbar spine and femoral neck by dual-energy X-ray absorptiometry. MAIN OUTCOME MEASURES: Variables associated with standardized BMD (sBMD) in adult-onset GHD were examined. RESULTS: In the LS, body mass index (r = 0.13, P < 0.01), unreplaced sex steroid deficiency (r = -0.17, P < 0.0001), and corticotropin deficiency (r = -0.11, P < 0.01) were independently associated with sBMD. In the FN, age (r = -0.19, P < 0.0001), female gender (r = -0.18, P < 0.0001), body mass index (r = 0.21, P < 0.0001), and decreased IGF-I SD scores (r = 0.10, P < 0.001) were independently associated with sBMD. CONCLUSIONS: Hormone variables associated with lower sBMD in patients with adult-onset GHD include unreplaced sex steroid deficiency and corticotropin deficiency in the LS and lower IGF-I SDS in the FN.

Physiological and pathological growth hormone secretion.

Growth hormone (GH) secretion is normally episodic, with discrete bursts of GH super-imposed on a minimal basal level of production. This pattern of GH production yields a dynamic state between a low baseline and intervening peaks, posing a challenge for the clinician attempting to understand the 'true GH status' in a specific patient. This pulsatile pattern is maintained throughout the day, but there are clear differences between different segments of the day, with approximately two-thirds of the total daily secretion produced at night. The dynamic nature of GH production has led many investigators to suggest that when evaluating short stature, parameters of spontaneous GH production be applied rather than the GH response to artificial stimulation. GH secretory patterns in healthy control populations are compared to those in patients with several conditions seen by the pediatric endocrinologist (classical GH deficiency, GH neurosecretory dysfunction, acute lymphoblastic leukemia, hypothyroidism, small for gestational age, Russell-Silver syndrome, constitutional delay of growth and puberty and Fanconi's anemia) and variables used for analysis of these patterns are described. Inferences made from comprehensive evaluations of the GH axis in Fanconi's anemia provide unique insight into general GH pathophysiology.

Effect of different growth hormone (GH) mutants on the regulation of GH-receptor gene transcription in a human hepatoma cell line.

OBJECTIVE: G to A transition at position 6664 of the growth hormone (GH-1) gene results in the substitution of Arg183 by His (R183H) in the GH protein and causes a new form of autosomal dominant isolated GH deficiency (IGHD type II). The aim of this study was to assess the bioactivity of this R183H mutant GH in comparison with both other GH variants and the 22-kDa GH in terms of GH-receptor gene regulation. DESIGN AND METHODS: The regulation of the GH-receptor gene (GH-receptor/GH binding protein, GHR/GHBP) transcription following the addition of variable concentrations (0, 12.5, 25, 50 and 500 ng/ml) of R183H mutant GH was studied in a human hepatoma cell line (HuH7) cultured in a serum-free hormonally defined medium. In addition, identical experiments were performed using either recombinant human GH (22-kDa GH) as a positive control or two GH-receptor antagonists (R77C mutant GH and pegvisomant (B-2036-PEG)) as negative controls. GHR/GHBP mRNA expression was quantitatively assessed by RT-PCR amplification after 0, 1, 3 and 6 h incubation. RESULTS: Following the addition of R183H mutant GH, GHR/GHBP mRNA changed at a similar rate to that seen in experiments where 22-kDa GH was added, indicating equal bioactivity. At all times and concentrations studied, the addition of R77C mutant GH, however, resulted in a significantly lower increase (P<0.001) of GHR/GHBP mRNA concentration compared with that caused by the addition of either 22-kDa GH or R183H mutant GH. Furthermore, in additional experiments, pegvisomant resulted in an absolute block of GHR/GHBP mRNA expression identical to that seen in control experiments where no 22-kDa GH was added at all. CONCLUSIONS: These data indicate that the R183H mutant GH, although causing an autosomal dominant form of IGHD has an identical effect on GHR/GHBP transcription as its wild-type, the 22-kDa GH. This implies that the IGHD caused by the R183H heterozygous mutation of the GH-1 gene is mainly due to a block of its regulated GH secretion. In addition, the R77C-GH variant and pegvisomant have an antagonistic effect at the level of GHR/GHBP transcription. All these data were confirmed by run-on experiments. In addition, these data highlight, as far as the GH variants are concerned, that a mutational alteration within the GH-1 gene might cause short stature also on the basis of an altered secretory pathway. This fact has to be taken into consideration when growth retardation is clinically diagnosed and studied at the molecular level. Secretory pathways and, therefore, cell-biological mechanisms are of importance and have to be considered in future not only at the scientific but also at the clinical level.