Patient-reported outcomes in patients with acromegaly treated with pegvisomant in the ACROSTUDY extension: A real-world experience.

PURPOSE: To report the effects of pegvisomant (PEGV) treatment on patient-reported outcomes in acromegaly patients. METHODS: We conducted an extension study of an open-label, multinational, non-interventional study (ACROSTUDY) evaluating the long-term safety and efficacy of PEGV for acromegaly in routine clinical practice. Enrolled patients were rollover patients from ACROSTUDY, or treatment naïve/semi-naïve (NSN; no PEGV within 6 months of enrollment). Exploratory efficacy endpoints were changes in symptoms with the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and quality of life with the Acromegaly Quality of Life questionnaire (AcroQoL) analyzed by controlled or uncontrolled IGF-I levels. Results were analyzed in all patients, in NSN patient subgroup, and by diabetes status. RESULTS: A total of 544 patients with acromegaly were enrolled, including 434 rollover subjects from ACROSTUDY and 110 NSN patients. Mean PEGV treatment duration was 7.8 years (range, 0-19.6 years). Overall, the majority of PASQ scores improved over time, but there was no significant difference between IGF-I controlled or uncontrolled groups. In the NSN subgroup, most PASQ and AcroQoL scores remained similar to baseline up to 1 year, regardless of IGF-I control. Patients with diabetes reported better PASQ scores over time with PEGV treatment, regardless of IGF-I control. IGF-I normalization increased from 10% of patients at baseline to more than 78% at year 10, with a mean daily PEGV dose of 18.7 mg. CONCLUSIONS: Overall, patients treated with PEGV had small improvements in PASQ. While IGF-I normalization increased with PEGV treatment, IGF-I control had no effects on PASQ and AcroQoL scores.

A Randomized, Cross-Over Study Investigating the Comparability of Somatrogon-ghla in 2 Different Drug Product Presentations.

Somatrogon-ghla is a long-acting, recombinant human growth hormone approved for the treatment of pediatric patients with growth hormone deficiency. Forty-nine healthy, adult males were enrolled in a randomized, crossover study to compare somatrogon exposure after subcutaneous doses administered using a frozen vial presentation or a prefilled, multiple dose pen. Somatrogon, insulin-like growth factor-I, and IGF-1 binding protein-3 concentrations were collected for up to 240 hours post dose to assess pharmacokinetic and pharmacodynamic responses. There was a 2-week washout between administration of the doses. Seven participants did not complete the study due to withdrawal of consent (n = 2) or loss to follow-up. Two treatment-emergent adverse events, headaches, were judged by the investigator as possibly related to study drug administration. Both were mild. Injection site reactions were observed in 6/48 participants after administration with the pen and 12/46 after administration using the vial. Drug and biomarker concentrations were assessed using validated assays and noncompartmental methods were used to determine pharmacokinetic and pharmacodynamic parameters. Bioequivalence was demonstrated for somatrogon area under the concentration-time curve, but not for the peak somatrogon concentration, where the lower limit of the 90% confidence interval for the ratio of pen/vial was 74.2%, which is less than the lower limit, 80.0%, dictated by bioequivalence criteria. The IGF-1 responses were largely within bioequivalence limits. It was concluded that the 2 formulations are comparable.

An overview of growth hormone therapy in pediatric cases documented in the Kabi International Growth Study (Pfizer International Growth Database).

The Kabi International Growth Study (KIGS) was first established in 1987 and is the largest pharmaco-epidemiological study of recombinant human growth hormone (rhGH). KIGS is aimed at evaluating long-term safety and treatment outcomes in pediatric subjects who received Genotropin rhGH therapy (Pfizer, New York, NY, USA) as prescribed by physicians in real-world clinical practice settings. KIGS data have been used to answer multiple research questions related to growth, growth prediction, and growth hormone treatment, leading to the publication of 129 peer-reviewed manuscripts and 24 biannual reports, outcomes from 10 expert meetings, and 3 books. The KIGS has shown that rhGH is safe and increases both the short-term height gain and adult height in patients with GH deficiency (GHD) and multiple other non-GHD conditions associated with short stature.

Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of once-weekly somatrogon with once-daily somatropin in children with GHD. METHODS: Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS. RESULTS: This post hoc subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children. CONCLUSIONS: This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.

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.

Persistence with daily growth hormone among children and adolescents with growth hormone deficiency in the UK.

Background: Children with growth hormone deficiency (GHD) are treated with daily somatropin injections; however, poor treatment persistence and adherence have been recognized previously and have been shown to negatively impact growth outcomes. A recent real-world study of a US pediatric GHD population found that a substantial proportion of children discontinued somatropin therapy, but similar data for a real-world UK population are lacking. Objectives: To describe the discontinuation of, and persistence with, daily somatropin treatment among children with GHD in the UK. Methods: This was a retrospective cohort study of children (≥3 and <16 years old) with ≥1 medication prescription for daily injectable somatropin from 1 July 2000 to 31 December 2020 in the IQVIA Medical Research DATA (IMRD) database. Early persistence was defined as the proportion of children prescribed ≥1 somatropin refill (≥2 prescriptions). Discontinuation was defined as the first date at which a medication gap for somatropin (of >60 or >90 days between prescriptions) occurred. Kaplan-Meier methods were used to evaluate persistence (non-discontinuation) over time to assess time to first discontinuation event. Cox proportional hazards models were used to evaluate the relationship between patient characteristics and time to medication discontinuation. Results: Among the cohort identified in this study (n = 117), the majority (n = 84, 71.8%) had 48 months of available follow-up; 56.4% were boys and the mean (median) age was 8.6 (8.0) years. About 98% exhibited early persistence, but persistence over the follow-up period decreased with follow-up duration. Using the conservative 90-day gap definition of persistence, an estimated 72.4%, 52.8%, and 43.3% were persistent at 12, 36, and 48 months. Lower persistence rates were observed using the 60-day definition. No significant patient predictors of time to discontinuation were identified. Conclusions: Despite high early persistence with somatropin, a high percentage of children with GHD were increasingly non-persistent over time. More than 1 in 4 were non-persistent at 12 months and more than 1 in 2 were non-persistent at 48 months of follow-up. These results suggest that strategies to support improved medication-taking behavior among children with GHD in the UK are warranted.

Suboptimal adherence to prescribed daily growth hormone regimen among medicaid beneficiaries in the United States.

OBJECTIVE: The objective of this retrospective cohort study was to describe the adherence and discontinuation patterns of somatropin over 3 years among children with pGHD insured by Medicaid across the United States. METHODS: Eligible children were aged ≥3 and <16 years with Medicaid coverage, diagnosed with pGHD, and had ≥2 new prescriptions for somatropin between 1 July 2014 and 31 December 2018. Four non-exclusive patient cohorts were constructed (≥3, 12, 24, and 36 months of continuous enrollment after initial prescription). Suboptimal adherence was defined as medication possession ratio <0.80, and discontinuation as a gap of >60 days between somatropin fills. Logistic and proportional hazards regression methods were used to estimate odds of suboptimal adherence and time to discontinuation, respectively. RESULTS: In the 12-month cohort (n = 3623), mean age was 10.5 ± 3.2 years, 70.8% were male, 44.4% White, 29.1% Hispanic, 7.1% Black, and 1.7% Asian. At months 12, 24, and 36, the proportion with suboptimal adherence was 40.9, 50.4, 54.4%, respectively, and 49.2% of patients with ≥3 months of follow-up discontinued therapy. At 12 months, lower age and race/ethnicity (Black vs. White referent) had greater odds of suboptimal adherence. Discontinuation was associated with Black (vs. White referent) race and geographic region. CONCLUSIONS: Sociodemographic characteristics may be risk factors for suboptimal adherence and/or discontinuation of prescribed somatropin therapy. Improving GH regimen adherence among this at-risk population, and specifically among subgroups at highest risk, is warranted to improve clinical outcomes.

Safety and effectiveness of taliglucerase alfa in patients with Gaucher disease: an interim analysis of real-world data from a multinational drug registry (TALIAS).

BACKGROUND: Limited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD). METHODS: Taliglucerase Alfa Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019. RESULTS: A total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients. CONCLUSIONS: The interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.

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.

Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study.

CONTEXT: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. METHODS: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. RESULTS: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). CONCLUSION: The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).

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.

Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor, exemestane.

BACKGROUND: Exemestane is an irreversible steroidal inhibitor of cytochrome-P450 aromatase required for estrogen synthesis. The safety of the drug in the pediatric population, particularly in males, has not previously been evaluated. Given the increased interest in treating children with aromatase inhibitors, we undertook a study in rats to assess the potential for exemestane to alter reproductive development and function when administered to juveniles. METHODS: Male and female rats were treated with exemestane at doses anticipated to produce exposures approximately 2- and 35-fold the expected clinical plasma exposure in young adult males during the period of reproductive maturation. After maturation, treated rats were mated to evaluate the potential impact on reproductive function. RESULTS AND CONCLUSION: There were no effects on sexual maturation in either sex or on female reproductive function. Treatment of juvenile male rats caused increased cohabitation time and decreased copulation rates; pregnancy rates and litter size were not affected in rats that mated. Decreased testis (10-15%) and epididymis (20-30%) weights, and decreased Sertoli cell numbers were noted at all doses. This indicates that exemestane can reduce Sertoli cell proliferation during maturation. The sensitive window for this effect is expected to be limited to the period of Sertoli cell proliferation, which is completed by around postnatal day 15 in rats and before puberty in humans. Treatment beginning at a later time relative to the window for Sertoli cell proliferation or for a longer duration is not expected to have additional adverse effect as the effect was not shown to be degenerative.

Suboptimal adherence to daily growth hormone in a US real-world study: an unmet need in the treatment of pediatric growth hormone deficiency.

OBJECTIVE: To evaluate adherence to, and discontinuation of, somatropin treatment over 4 years in a US population-based study of children with pediatric growth hormone deficiency (pGHD). METHODS: A retrospective cohort analysis of commercially insured patients ≥3 and <16 years, diagnosed with pGHD, newly treated with somatropin was conducted using Optum De-identified Clinformatics Data Mart. Index date was defined as the first prescription for somatropin between 01 July 2002 and 30 September 2019. Five non-exclusive patient cohorts were identified (>3, 12, 24, 36, and 48 months of post-index continuous enrollment). Suboptimal adherence was defined as medication possession ratio <80%. Discontinuation was defined as the date at which a gap of >60 days between somatropin fills first occurred. Cox proportional hazards regression was used to evaluate time to discontinuation. RESULTS: In the 12-month cohort (n = 3091), mean age was 11.3 ± 2.9 years, 75.9% were male, 70.9% white, 9.4% Hispanic, 3.6% Asian, and 3.1% black. The proportion with suboptimal adherence at months 12 and 48 was 19.6% and 35.9%, respectively. Discontinuation occurred in 42.2% of patients. The rate of discontinuation (HR [95% CI]) was higher for age ≥10 (1.74 [1.53-1.98]), females (1.35 [1.21-1.50]), black and Hispanic race/ethnicity (1.50 [1.18-1.90] and 1.27 [1.09-1.49] compared to White) and obesity (1.69 [1.19-2.40]). CONCLUSION: Suboptimal adherence increases with treatment duration, and risk of discontinuation is associated with age, female gender, black or Hispanic race/ethnicity, and obesity. Strategies that facilitate adherence among children at risk of discontinuation may improve clinical outcomes.

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.

A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.

CONTEXT: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. OBJECTIVE: To identify genetic variants associated with GH responsiveness. DESIGN: Genome-wide association study (GWAS). SETTING: Cohorts from multiple academic centers and a clinical trial. PATIENTS: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. INTERVENTION: Association of more than 2 million variants was tested. MAIN OUTCOME MEASURES: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. RESULTS: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. CONCLUSIONS: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.

Gender of pediatric recombinant human growth hormone recipients in the United States and globally.

BACKGROUND: Gender disparities were found in reports of early pediatric recombinant human GH (rhGH) use in the United States. With rhGH entering its third decade, we sought to examine U.S. gender-based treatment patterns and how these patterns compare with that of other countries. METHODS: All children entered in the Pfizer International Growth Study, a database designed to document long-term outcomes and safety of Genotropin (Pfizer, New York, NY), were categorized by gender, location, date and age of therapy initiation, and diagnosis. Measures of national health status, health care expenditure, general economic indices, and mean adult heights were also compared. RESULTS: Throughout the past 20 yr, the United States had an almost 2:1 male to female ratio overall. The gender ratio depended on the specific indication and age. There was no consistent relation to geographical region, pediatric population size, or density of pediatric endocrinologists. Male predominance was seen in Asia (mostly Japan), the United States, and Europe/Australia/New Zealand (65, 64, and 55%, respectively), but not the rest of the world (47%), where rhGH was prescribed less frequently. In the countries with the greatest rhGH use, the gender ratios depended on the specific indications but did not correlate with mean adult height, national health care measures, or general economic indices. CONCLUSIONS: Male predominance among U.S. pediatric rhGH recipients persists, especially for indications without a clear organic etiology. Global differences in gender ratios suggest that factors other than biology are at play. We speculate that social and cultural pressures and the health care systems' permissiveness toward paying for rhGH therapy contribute to these international differences.

Predictors of first-year growth response to a fixed-dose growth hormone treatment in children born small for gestational age: results of an open-label, multicenter trial in the United States.

BACKGROUND: Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM: To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS: 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS: Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION: GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene.

CONTEXT: G to A transition at position 6,664 (G6664A) in human GH-1 results in the substitution of arginine by histidine at position 183 (R183H) of the GH molecule and causes familial isolated GH deficiency type II (IGHD II). OBJECTIVES: The objective of the study was to assess the phenotype-genotype correlation of subjects affected with IGHD II caused by a G6664A mutation in 34 affected members of two large families. DESIGN AND PATIENTS: Sixty-six subjects from two core families were included. The G6664A mutation among family members was determined by restriction fragment length polymorphism. RESULTS: Twenty-four of the 52 members from family 1 and 10 of 14 from family 2 carried the same G6664A mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter [-2.6 vs. -0.1 sd score (SDS), P < 0.0001] and had significantly lower IGF-I serum levels (-1.9 vs. -0.5 SDS, P < 0.0001), compared with normal-genotype family members. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 (mean -2.8 SDS), with five members being of normal height (>-2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although one of these subsequently demonstrated GH insufficiency (6.5 and 3.7 ng/ml). The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age (chronological age - bone age), age at diagnosis, peak GH response, and IGF-I levels. CONCLUSIONS: These detailed phenotypic analyses show the variable expressivity of patients bearing a G6664A mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. Our findings raise a new dilemma in the guidelines for the diagnosis of GH deficiency and the indications for GH therapy.

Treatment of acromegaly with pegvisomant during pregnancy: maternal and fetal effects.

OBJECTIVE: Our objective was to describe the first case of the successful use of pegvisomant during pregnancy in a woman with acromegaly. DESIGN: We present the case of a 26-yr-old female with acromegaly who had failed surgical and subsequent medical therapy but whose disease was well controlled on pegvisomant. She then conceived and was continued on pegvisomant throughout pregnancy. We then collected both maternal and cord blood samples at parturition, and later analyzed her breast milk. RESULTS: Maternal IGF-I was well controlled during gestation. Fetal GH and IGF-I were within the normal range. Maternal pegvisomant levels were consistent with a 25-mg daily dosage. Fetal pegvisomant levels were minimal and near the range detected in untreated acromegalic patients, likely representing minimal cross-reactivity from endogenous GH or spurious contamination by maternal blood. GH variant levels in the maternal blood and the cord blood were both within the normal ranges. Pegvisomant levels in breast milk were below the lower limit of quantification of the assay and similar to those observed when analyzing breast milk samples from normal mothers in the same assay. Fetal growth parameters were normal; the baby was healthy and showed no adverse signs. CONCLUSIONS: Pegvisomant therapy during gestation was safe and effective in our patient. Transplacental passage of pegvisomant is either absent or minimal, with a concentration highly unlikely to convey any significant pharmacodynamic effects on the fetal GH and IGF-I system. In addition, there is no evidence of substantial secretion of pegvisomant into breast milk.