Daily hGH Research Articles

PMON336 Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES): A multi-country, non-interventional, prospective, cohort study of patients receiving human growth hormone treatments under routine clinical care

Abstract Background Children with growth hormone deficiency (GHD) are treated with recombinant human growth hormone (rhGH), usually administered as a daily subcutaneous injection. Long-acting hGH (LAGH) treatments (approved and in development) have the potential to improve adherence and treatment outcomes. Somatrogon is a LAGH currently being developed as a once-weekly injectable treatment for GHD. The Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES) study was initiated to assess the long-term safety and effectiveness of Genotropin and other hGH formulations to treat GHD under routine clinical care. Goals & aims: The overall goal of the registry is to increase our understanding of hGH treatments as used in a real-world setting. Enrolling children treated with different daily hGH brands as well as somatrogon (if approved in a given geography) will enable comparison between daily and LAGH, and across daily hGH brands. The primary objectives of the study are to describe and compare the safety and effectiveness of daily and LAGH treatments in children. Secondary objectives include evaluating adherence to hGH treatments and the health-related quality of life (HRQoL) and treatment experience of patients receiving hGH treatments. Methods For this non-interventional, prospective, phase 4 cohort study, eligible patients (male or female at any age) from >20 countries are planned for inclusion, with the aim of targeting 667 patients across the daily hGH brands in each of the three geographic regions. Patients will be enrolled from September 2021 to October 2029, with data collection planned until October 2030. Study inclusion criteria include prescription of daily Genotropin or other approved hGH treatments for GHD and the provision of informed consent/assent. If somatrogon is approved by regulatory agencies, somatrogon-treated patients will also be eligible for inclusion. Patients participating in any interventional clinical trials at the time of enrollment will be excluded from the study. Patients will be followed until the end of the study, withdrawal of consent, death, switch to an excluded hGH, or loss to follow-up, whichever occurs first. In addition to demographic and clinical characteristics, information on hGH treatment brand, dose and start/end dates will be collected, along with reasons for switching or discontinuing treatment. Primary safety outcomes include adverse events (AEs), serious AEs, and AEs of special interest. Primary effectiveness outcomes include annual height velocity (HV) and change in HV standard deviation scores. Treatment adherence, compliance outcomes, HRQoL, and patient treatment experience will be assessed. Conclusions The findings from the PROGRES study will provide valuable insights into the use of somatrogon, Genotropin and other approved hGH treatments in real-world clinical practice, specifically with regard to the long-term safety and effectiveness of these treatments as well as treatment compliance and patient HRQoL. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON329 Survey of physician experience with once weekly somatrogon vs once daily somatropin regimen for the treatment of pediatric patients with growth hormone deficiency: results from a cross sectional, observational study

Abstract Background Somatrogon is a long-acting recombinant human growth hormone (hGH) currently being developed as a once-weekly subcutaneous injectable treatment for pediatric patients with growth hormone deficiency (GHD). A recent global Phase 3 study compared the efficacy and safety of somatrogon administered once weekly with Genotropin administered once daily in pediatric patients with GHD (ClinicalTrials.gov: NCT02968004). Aims To understand and describe physicians’ experiences using once-weekly somatrogon injections compared with once-daily hGH injections during the Phase 3 study. Methods In this quantitative, cross-sectional, observational study, a 14-item multiple choice questionnaire was administered to physicians who were clinical investigators in the Phase 3 study. The questionnaire was designed to assess physicians’ experiences, preferences and satisfaction regarding the use of the once-weekly somatrogon regimen compared with the standard once-daily hGH injection regimen. Survey results were analyzed quantitatively using descriptive statistics. Results A total of 24 physicians who were part of the global Phase 3 study (mean age [SD]: 58.5 [10.1] years; 10 males, 14 females) in 12 different countries completed the on-line survey. Compared with daily injections, most physicians preferred somatrogon (n=18, 75.0%) and reported that somatrogon was more convenient (n=19, 79.2%), less burdensome (n=19, 79.2%) and that they would be more likely to prescribe somatrogon to patients in the future (n=20, 83.3%). In terms of being more likely to support positive long-term growth outcomes, 37.5% (n=9) of physicians selected somatrogon; the remaining physicians (n=15, 62.5%) reported no difference between treatments. The proportion of physicians who were satisfied or very satisfied with somatrogon was 95.8% (n=23), compared with 87.5% (n=21) for daily hGH injections. Most physicians (n=15, 62.5%) reported that daily hGH injections required more effort/much more effort to monitor adherence, compared with somatrogon. Some physicians (n=7, 29.2%) reported that explaining the device instructions to patient/caregivers required more/much more effort for somatrogon compared with daily hGH injections; more than half (n=14, 58.3%) reported no difference in effort required for either regimen. Physicians were divided as to which treatment needed more/much more effort to: (i) explain the injection regimen (n=7 [29.2%] daily injection; n=7 [29.2%] no difference; n=10 [41.7%] somatrogon), (ii) explain what to do if an injection is missed (n=7 [29.2%] daily injection; n=9 [37.5%] no difference; n=8 [33.3%] somatrogon), and (iii) address patient/caregiver questions (n=8 [33.3%] daily injection; n=11 [45.8%] no difference; n=5 [20.8%] somatrogon). Conclusions Overall, physicians from the global Phase 3 study were positive about their experience using somatrogon for the treatment of children with GHD. Physicians generally preferred the once-weekly somatrogon injection regimen, with most physicians reporting somatrogon to be more convenient and less burdensome to patients, indicating that they would be more likely to prescribe somatrogon to their patients in the future. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Perception of Adherence to Daily Human Growth Hormone Treatments Among Pediatric and Adolescent Patients in Japan: A Cross-Sectional Survey of Physicians and Caregivers.

Poor adherence to daily human growth hormone (hGH) treatment has been shown to be associated with poor clinical outcomes for growth hormone deficiency (GHD) patients. However, few studies have examined the perception of adherence to hGH treatment among both physicians and caregivers in Japan. The aim of this study is to examine the perception of adherence for daily hGH treatment among physicians and caregivers of pediatric and adolescent patients treated with GH in Japan. Moreover, we explore reasons for skipping treatment and the potential impact of a once-weekly treatment on adherence. A cross-sectional survey was conducted in Japan among physicians that prescribe daily hGH treatment and caregivers that have administered daily hGH treatment to children/adolescents for 3 months or longer. The Morisky Medication Adherence Scale (MMAS-8) was used to gauge perceived adherence for both physician and caregiver groups. Caregivers were also questioned regarding reasons for missing injections. Moreover, both groups were asked about the impact of a once-weekly treatment on adherence. Responses were collected from 123 physicians and 112 caregivers. Physicians reported that 18.1% of patients have poor adherence based on the MMAS-8 instrument. In contrast, 32.1% of the caregivers reported poor adherence. "Simply forgetting", "Patient refused/resisted", and being "Busy with school activities, etc" were the most commonly selected reasons by caregivers for missing an injection. Physicians felt that a once-weekly injection could improve adherence for 64.5% of patients with poor adherence. Moreover, 56.9% of the caregivers that reported an experience of missed injections felt that a once-weekly injection would improve their adherence. Approaches to improve adherence to hGH treatment in Japan are continuously needed. While further research is needed to understand factors most likely to improve adherence, availability of a once-weekly treatment is expected to help improve adherence.

OR10-05 Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

Background: The Phase 3 fliGHt Trial evaluated children with growth hormone deficiency (GHD) of a broad range of baseline demographics and treatment durations who switched from daily growth hormone (hGH; somatropin) therapy to once-weekly TransCon hGH. TransCon hGH is an investigational long-acting prodrug consisting of 3 components: hGH, an inert carrier that protects it, and a linker that temporarily binds the two. When injected into the body, at physiologic pH and temperature, unmodified hGH is gradually released in a predictable manner. Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. The primary objective was to assess safety and tolerability over this 26-week trial. Efficacy measures included annualized height velocity (AHV), height standard deviation score (SDS), and insulin-like growth factor 1 (IGF-1) SDS. Results: Of the 146 enrolled subjects, 98.6% completed the trial. Mean age at baseline was 10.6 years (range: 1, 17). The majority (97.9%) were treatment-experienced with a prior daily hGH mean dose of 0.29 mg/kg/week (range: 0.13, 0.49); 3 subjects were treatment-naïve and <3 years old. Just over half the subjects (56.8%) experienced a treatment-emergent adverse event (TEAE), with only 4.1% of subjects experiencing a TEAE considered related to study drug. No TEAE led to discontinuation of study drug. The type and frequency of TEAEs reported were similar to the published adverse event profile of daily hGH therapies. Mean hemoglobin A1c remained 5.2% at baseline and Week 26. No neutralizing antibodies were detected; low-titer anti-hGH binding antibodies were detected in 2.8% of subjects. Growth outcomes were as expected for this treatment-experienced heterogenous population, with a least-squares mean (LSM) AHV of 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). In the age-defined subgroups, mean observed AHV at Week 26 ranged from 8.2 to 16.2 cm/year and mean observed height SDS change from baseline to Week 26 ranged from +0.23 to +0.96. Of note, the linear relationship between average IGF-1 SDS and TransCon hGH doses demonstrated in previous treatment-naïve trials was preserved in this population of treatment-experienced children who had dose titrations. Conclusions: TransCon hGH treatment outcomes, including AHV and height SDS, were as expected across a diversity of ages, disease characteristics, and treatment experiences, reflective of a real-world setting. Dose titrations of TransCon hGH demonstrated a predictable IGF-1 response. Switching to TransCon hGH resulted in a similar adverse event profile to daily hGH therapy.

SAT-LB16 Maintenance of Favorable Treatment Effect of Once-Weekly TransCon hGH for Children With Growth Hormone Deficiency: Interim Analysis From the Enlighten Long-Term Extension Trial

Background Once-weekly TransCon hGH is an investigational long-acting prodrug for growth hormone deficiency (GHD) that consists of 3 components: unmodified growth hormone (hGH; somatropin), an inert carrier that protects it, and a linker that temporarily binds the two. In the randomized phase 3 heiGHt Trial evaluating treatment-naïve children with GHD, TransCon hGH demonstrated superior annualized height velocity and ∆ height standard deviation score (SDS) compared to Genotropin and had a similar safety and tolerability profile. Methods Results are reported from an interim analysis of subjects from heiGHt who continued in the ongoing enliGHten long-term extension trial for 26 weeks. In the 52-week heiGHt Trial, treatment-naïve, prepubertal subjects with GHD were randomized 2:1 to receive once-weekly TransCon hGH 0.24 mg hGH/kg/week or an equivalent weekly dose of daily Genotropin. Subjects completing heiGHt could enroll in enliGHten, where all subjects received TransCon hGH. Two groups were analyzed: Group A (TransCon hGH in both heiGHt and enliGHten) and Group B (Genotropin in heiGHt, followed by TransCon hGH in enliGHten). Safety and growth outcomes were evaluated approximately every 13 weeks in heiGHt and enliGHten. IGF-1 was sampled on postdose Day 5 (±1 day) in enliGHten. A by-visit ANCOVA model was used to analyze numeric efficacy endpoints.ResultsAll but one subject who completed heiGHt continued into enliGHten (A: N=103, B: N=55). Baseline characteristics at the start of heiGHt were balanced between groups. The statistically significant treatment difference in ∆ height SDS (Group A vs B) at the end of heiGHt (Week 52, N=159; 1.10 vs 0.96, P=0.0149) was sustained through Week 78 (N=154; 1.39 vs 1.24, P=0.0436), demonstrating persistence of catch-up growth for both groups and maintenance of superior treatment effect for subjects treated with TransCon hGH in the first year of therapy. At Week 78, least-squares mean (SE) IGF-1 SDS on postdose Day 5 (N=153) was 0.52 (0.15) for Group A and 0.59 (0.19) for Group B. Adverse events (AEs) were comparable between groups during heiGHt. During enliGHten, 48.7% (76/156) and 1.9% (3/156) of subjects experienced AEs and serious AEs, respectively; the AE profile was consistent with what was previously observed in heiGHt. A low titer of anti-hGH binding antibodies were detected in 10/156 (6.4%) subjects during treatment with TransCon hGH in heiGHt and enliGHten; no neutralizing antibodies were detected. Lab parameters (HbA1c, cortisol, free thyroxine) were stable and generally remained within the normal range throughout the trials. Mean (SD) BMI SDS was 0.0 (0.8) for Group A and 0.1 (0.9) for Group B at Week 78.Conclusions Children treated with TransCon hGH showed continued improvement of height SDS beyond the first year. Treatment with TransCon hGH through 78 weeks demonstrated an AE and immunogenicity profile comparable to that of a daily hGH therapy.

OR10-06 Somatrogon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Pediatric Phase 3 Clinical Trial

Background: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone (rhGH; somatropin) in development for once weekly treatment of children with growth hormone deficiency (GHD). Somatrogon contains the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) derived from human chorionic gonadotropin. A 12 month phase 2 trial of once weekly Somatrogon vs daily Genotropin in children with GHD demonstrated that 0.66 mg/kg/wk of Somatrogon had a similar benefit - risk profile as 0.24 mg/kg/wk of Genotropin. The open label extension of this phase 2 study has generated an additional 5 years of longitudinal efficacy and safety data with this dose. This report summarizes top line results from a pivotal phase 3 global trial (ClinicalTrials.gov: NCT02968004) designed to investigate the non-inferiority of once weekly Somatrogon hGH-CTP compared to daily hGH after 12 months in treatment-naive prepubertal children with GHD. Methods: The Phase 3 trial enrolled 224 subjects who were randomized in a 1:1 ratio to receive either once weekly Somatrogon hGH-CTP (0.66 mg/kg) or once daily Genotropin (0.24 mg/kg/wk) for 12 months. Randomization was stratified by geographic region, peak GH level and age. The primary endpoint of the study was height velocity (HV) at month 12; secondary endpoints included HV at month 6, change in height SDS at month 6 and 12, IGF-1 and IGF-I SDS, immunogenicity, and safety. Results: At baseline, the mean (SD) age and height SDS of the somatrogon (N=109, 75.2% male) and Genotropin (N=115, 68.7% male) groups were 7.83 (2.66) and -2.94 (1.29) and 7.61 (2.37) and -2.78 (1.27), respectively. One subject in each group discontinued during the 12 month study, and 95% of the completers continued into an open-label extension study. At month 12, mean HV was 10.12 cm/yr in the Somatrogon group and 9.78 cm/yr in the Genotropin group, with the treatment difference of 0.33 cm/year favoring Somatrogon. The lower bound of the two-sided 95% confidence interval of the treatment difference was -0.39, which was higher than the pre-established non-inferiority margin and demonstrated non-inferiority of once weekly somatrogon vs daily Genotropin therapy. Height velocity at month 6 (10.60 cm/yr vs 10.04 cm/yr), change in height SDS at months 6 (0.54 vs 0.48) and 12 (0.92 vs 0.87) were likewise numerically higher in the Somatrogon-treated cohort. The majority of adverse events were mild to moderate in severity (somatrogon: 78.9%, Genotropin: 79.1%) and, overall, weekly somatrogon was generally well-tolerated and comparable to daily Genotropin. Conclusion: Top-line results from the pivotal phase 3 trial demonstrate that Somatrogon (hGH-CTP) given once weekly by sc injection is non-inferior to Genotropin (hGH) given once daily and that once weekly somatrogon administration was generally well-tolerated in patients with pGHD.

Treatment Experience of Children with Growth Hormone Deficiency in the Phase 3 fliGHt Trial: Switching from Daily Growth Hormone to Once-weekly TransCon hGH

Background: Patients treated with daily growth hormone (hGH; somatropin) therapy have long requested the option of a treatment requiring fewer injections. Once-weekly TransCon hGH is an investigational long-acting prodrug in development for the treatment of growth hormone deficiency (GHD) designed to fulfill this unmet need. TransCon hGH consists of 3 components: unmodified hGH, an inert carrier that protects it, and a linker that temporarily binds the two. Aims: To evaluate preference and treatment burden of patients and parents/caregivers in the Phase 3 fliGHt Trial of children with GHD treated with once-weekly TransCon hGH who switched from daily growth hormone therapy. Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week (via vial and syringe) irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated previously with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. To assess preference and treatment burden, subjects ≥9 years old (C) and all parents/caregivers (P) completed the Preference Questionnaire (PQ-C/P) at Weeks 6 and 13, and Child Sheehan Disability Scale (CSDS-C/P) at baseline, Weeks 6, 13, and 26. Results: The most common daily hGH treatments that subjects used previously were Norditropin FlexPro (31%), Nutropin AQ Nuspin (19%), HumatroPen (17%), and Omnitrope Pen (17%). The majority of subjects and parents/caregivers preferred TransCon hGH over their previous daily hGH treatment, and this preference increased with continued use (74.0% and 87.7% at Week 6 and 83.8% and 90.1% at Week 13, respectively); the most important reason for this preference in both groups was the reduced frequency of injections. Treatment burden, as assessed by the CSDS-C/P, decreased from baseline to Week 26 (C:2.5 to 1.4 and P:5.7 to 1.9) with weekly TransCon hGH treatment. Conclusions: In the fliGHt Trial, once-weekly TransCon hGH was the preferred treatment option for children with GHD and reduced the treatment burden for both children and parents/caregivers relative to prior daily hGH treatments.

OR17-4 Transcon Growth Hormone In The Treatment Of Pediatric Growth Hormone Deficiency: Results Of The Phase 3 Height Trial

TransCon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Phase 3 heiGHt Trial Background TransCon Growth Hormone is a sustained-release recombinant human growth hormone (hGH; somatropin) prodrug in development as a long-acting GH (LAGH) for children with growth hormone deficiency (GHD). In its prodrug form, TransCon hGH is inactive with hGH transiently bound to a TransCon carrier via a TransCon linker. Upon injection and triggered by physiological pH and temperature, unmodified recombinant hGH is sustainably released and thus designed to maintain the same mode-of-action and distribution as daily hGH replacement therapy but with once-weekly dosing. In a 6-month phase 2 trial of TransCon hGH vs. a daily hGH in children with GHD, mean annualized height velocity (AHV) for TransCon hGH was 12.9 cm/y compared to 11.6 cm/y for a daily hGH at an equivalent hGH dose (0.21 mg/kg/wk). The subsequent pivotal phase 3 global heiGHt Trial (ClinicalTrials.gov: NCT02781727) was designed to investigate the safety, tolerability, and efficacy of weekly TransCon hGH versus daily hGH over 52 weeks in treatment-naive prepubertal children with GHD. Methods Subjects were randomized in a 2:1 ratio and received either once-weekly TransCon hGH 0.24 mg hGH/kg/wk or dose-equivalent once-daily Genotropin over 52 weeks. Key baseline demographics variables included age, gender, height standard deviation score (SDS), IGF-1 SDS, peak stimulated GH, and bone age delay. Study endpoints included AHV, IGF-1 response, immunogenicity, and safety. Results At baseline, the mean age of study participants, of whom 82% were male, was 8.5 years. Mean height SDS was -2.93, and mean IGF-1 SDS was -2.04. Mean peak stimulated GH was 5.77 µg/L, and mean bone delay was 2.63 years. The final sample size (n=161) was larger than planned (n=150) which strengthens the study power for noninferiority. Top-line results, including AHV, change in height SDS, serum IGF-1 levels, change in bone age, and adverse events, will be available for presentation at ENDO 2019. Conclusion Only LAGHs based on unmodified hGH have obtained approval in Europe or the United States. By February 2019, all subjects will have completed their participation in this pivotal trial of a LAGH designed to release unmodified hGH, with top-line analyses available in March. The heiGHt Trial was well-powered to demonstrate noninferiority between TransCon hGH and a daily hGH, with baseline demographic variables in the range of recent GH trials.

Chemical and Enzymatic Site Specific PEGylation of hGH: The Stability and in vivo Activity of PEG‐N‐Terminal‐hGH and PEG‐Gln141‐hGH Conjugates

The use of therapeutic proteins is often impaired by their short in vivo half-lives. PEGylation has been exploited to enhance protein stability and to prolong the pharmacokinetic. The biophysical characterization of two site-specific mono-PEGylated forms of human growth hormone (hGH)--chemically N-terminal PEGylated hGH (PEG-Nter-hGH) and enzymatically Gln141 PEGylated hGH (PEG-Gln141-hGH) via transglutaminase--is outlined here and their pharmacodynamics are compared. The thermal stability of PEG-Nter-hGH was increased with respect to that of hGH and PEG-Gln141-hGH. Pharmacodynamic studies in rats showed that a single injection of the conjugates had a better or comparable potency with respect to a daily hGH on a week schedule in terms of weight gain, femoral length, and tibial diaphysis width.

OR03-6 Intranasal administration of Human Growth Hormone (CP024) and induction of IGF-1 in healthy volunteers

Results: All dose-levels of ACP-001 were safe and well tolerated. Most frequent AEs were headache and fatigue. Two SAEs occurred in one patient, judged as not drug-related. A total of nine patients experienced injection site reactions, the most frequent being mild erythema and reported across all treatment groups. No lipoatrophy at the injection site was observed. No treatment emergent antibodies occurred. Data showed pharmacokinetic and pharmacodynamic dose-response of the different dose levels of ACP-001. IGF-I levelsincreased in a dose-dependent manner and demonstrated a similar response for ACP-001 0.04mg/kg/week compared to the corresponding dose of daily hGH (0.04mg/kg/week). Conclusion: ACP-001 was safe and well tolerated in this Phase 2 study in adult patients with GrowthHormone Deficiency. Pharmacokinetic results support a once-weekly dosing. IGF-I increased in a dose-dependent manner and comparable to daily hGH, indicating that ACP-001 is at least as potent as the corresponding dose of daily hGH.

Adult height of prepubertal short children born small for gestational age treated with GH

Human GH (hGH) treatment leads to catch-up growth in children with short stature born small for gestational age (SGA). However, long-term efficacy and safety results in this patient group remain scarce. The present study assessed the efficacy and safety of late childhood treatment with biosynthetic hGH (Humatrope) in a group of short children born SGA (height <-2 standard deviation scores (SDS)). Patients in this open-label, Phase III, multicenter study received a daily hGH dose of 0.067 mg/kg for 2 years, and then received no treatment for the following 2 years. After the fourth year on study, patients whose height had decreased more than 0.5 SDS but who still showed growth potential based on bone age were allowed to resume treatment until they reached adult height. Height gain SDS was assessed for 11 girls and 24 boys (mean age+/-s.d. 9.6+/-0.9 years) at the end of the 2 years of hGH treatment, during the subsequent 2-year off-treatment period, and upon reaching adult height. At the end of the initial 2-year treatment period, 83% of patients had reached a height within the normal range, with a mean increase in height SDS vs baseline of 1.3+/-0.3 (P <0.001). Adult heights (n = 20) were within the normal range for 50% of patients, and mean height gain from baseline was statistically significant (0.7+/-0.8 SDS, P <0.001). Fasting glucose and glycosylated hemoglobin levels were not significantly modified during treatment. High-dose hGH treatment for a minimum of 2 years in short children born SGA was well tolerated and resulted in a significant increase in adolescent and adult height.

The sensitivity of hepatic CYP2C gene expression to baseline growth hormone (GH) bioactivity in dwarf rats: effects of GH-binding protein in vivo.

Hepatic mRNA transcripts for the steroid-metabolizing enzymes cytochrome P4502C11 (male specific) and P4502C12 (female specific) differ in abundance by 10- to 20-fold in male and female rats and are regulated by their different patterns of GH secretion. This sex difference is also found in dwarf rats with low GH secretion, implying that these transcripts may be very sensitive to low level GH exposure. This has now been characterized in normal and dwarf rats. Continuous i.v. infusion of recombinant human (h) GH (0, 3, 12, and 48 micrograms/day) in both dwarf and normal male rats caused a dose-dependent decrease in P4502C11 and an increase in P4502C12, so that the 2C11/2C12 ratio fell from 17.9 +/- 1.3 to 1.5 +/- 1.0 in normal males and from 6.5 +/- 0.9 to 0.4 +/- 0.3 in dwarf males (0 vs. 48 micrograms hGH/day); over this dose range of hGH, body weight gain, total hepatic insulin-like growth factor-I mRNA levels, and plasma GHBP levels were largely unaffected. These effects of hGH were pattern dependent. The 2C11/2C12 ratio in dwarf males was feminized (from 11.9 +/- 1.3 to 0.08 +/- 0.03) by continuous infusion of hGH (36 micrograms/day), whereas a pulsatile infusion (3-min pulses every 3 h) of the same daily hGH dose was much less effective. Neither continuous nor pulsatile hGH affected P4502C11 or P4502C12 transcripts in dwarf females, although pulsatile hGH infusion caused a significant weight gain. To test whether baseline GH levels could be modified by circulating GH-binding protein (GHBP), hGH infusions were given with and without recombinant hGHBP in different patterns. Pulsatile infusions of recombinant hGHBP (42 micrograms/day, i.v.) did not prevent the feminizing effect of continuously infused hGH (36 micrograms/day, sc) in dwarf males (2C11/2C12 ratios were 0.08 +/- 0.01 and 0.09 +/- 0.01 for hGH vs. hGH plus hGHBP, respectively). This suggested that intermittent complex formation with GHBP did not prevent continuous access of hGH to the hepatic GH receptors. Furthermore, pulses of hGH complexed with GHBP significantly reduced the 2C11/2C12 ratio in dwarf males (from 21.5 +/- 3.9 with pulsatile hGH alone to 9.2 +/- 2.5 with pulses of hGH plus hGHBP), indicating that GHBP prolongs the exposure to hGH. Thus, 2C11/2C12 expression is very sensitive to basal GH levels in dwarf rats, and GHBP can alter hepatic gene expression by modifying the pattern of GH exposure.

Low-dose amino acid supplementation: no effects on serum human growth hormone and insulin in male weightlifters.

Using a double-blind, crossover protocol, we studied the possible effects of a 4-day combined L-arginine, L-ornithine, and L-lysine supplementation (each 2 g/day, divided into two daily doses) on 24-hr level of serum human growth hormone (hGH) and insulin in 11 competitive weightlifters, ages 19 to 35 yrs. Three similar daily hGH peaks, seemingly preceded by a decrease in serum insulin concentration, were found during both amino acid and placebo supplementation. Supplementation did not affect the physiological variation of serum hGH concentration (treatment and treatment x time interaction: p = 0.43-0.55). Analogously, serum insulin levels were not higher after amino acid supplementation. Therefore the ergogenic value of low-dose oral amino acid supplementation in increasing hGH or insulin secretion seems questionable.

Urinary Human Growth Hormone Measurement Using a Highly Sensitive Sandwich Enzyme Immunoassay: Diagnostic and Therapeutic Uses in Patients with Growth Hormone Deficiency*

Several reports indicate that urinary hGH excretion is significantly lower in patients with either partial (PGHD) or complete GH deficiency (CGHD) than in normal but short children (NSC) or normal children (NC). However, there is an overlap between the NSC and NC groups and the PGHD group. Using a highly sensitive sandwich enzyme immunoassay, we investigated whether the measurement of urinary hGH can clearly separate the PGHD and CGHD groups from the NSC and NC groups. In addition, we measured the urinary excretion of synthetic methionyl-hGH (met-hGH) in PGHD and CGHD after sc injections of 2 and 4 IU and im injections of 4 IU in an attempt to determine the optimal replacement dose. Total 24-h urinary hGH excretion in each patient examined for 2 consecutive days varied from 1 day to the next. There were no differences in urinary hGH excretions between the NSC group and the NC group. The lower values for daily urinary hGH excretion in the NSC group overlapped some of the higher values in the PGHD group. However, when the mean urinary hGH level of both days was used, the 24-h urinary hGH excretion clearly separated the PGHD (5.5 +/- 2.3 ng/day; range, 1.3-9.2; n = 21) and CGHD (1.9 +/- 0.9 ng/day; range, 0.6-3.6; n = 14) groups from the NSC (12.8 +/- 3.1 ng/day; range, 9.3-17.5; n = 10) and NC (14.6 +/- 3.1 ng/day; range, 10.6-19.0; n = 6) groups without any overlap. A mean urinary hGH value less than 9.0 ng/day during a 2-day collection strongly suggested GH deficiency. Ten of 16 patients with PGHD and CGHD who received 2 IU met-hGH, sc, had urinary hGH levels within the range of the mean +/- SD in NSC. These patients received daily sc 0.097 +/- 0.024 IU/kg hGH injections. These results suggest that the measurement of 24-h urinary hGH excretion is noninvasive, accurate, and useful for the screening of GH deficiency. The mean value on 2 days of 24-h urinary hGH excretion for the screening of GH deficiency is estimated to be less than 9.0 ng/day. The optimal dose of GH as therapy for GH deficiency is demonstrated as daily sc injection of 0.1 IU/kg hGH, 0.7 IU/kg/week. To convert international units of met-hGH to milligrams, divide by 2.4.

The Effect of Human Growth Hormone Injection Frequency on Linear Growth Rate

hGH has been used in the treatment of hGH deficient children for nearly 30 years. The optimum treatment regimen is, however, still unknown. Generally, administration has been by 2 or 3 intramuscular injections/week and the total weekly dose has been 0.3-0.5 IU/kg. Many factors are known to influence the effect of treatment, such as the dose and the age of the child. In animal studies, the optimum growth rate occurs when the physiological pulse frequency of growth hormone is simulated (i.e. intravenous infusions of growth hormone every 3 hours in the rat). In humans, optimal growth rates occur in children in whom the spontaneous secretion of hGH is associated with many peaks (pulses) of high amplitude. In hGH deficient children, growth rate increases when the weekly dose of hGH is administered daily rather than 2-3 times/week, thereby optimizing the body's utilization of the hormone. The hGH plasma profile after daily subcutaneous hGH injections is, however, different from the hGH plasma profiles of children growing normally, in whom hGH secretion is episodic with many sharp pulses during the day and night. Whether simulation of normal hGH plasma profiles will increase the growth rate in hGH deficient children and normalize their adult height requires further investigation.

HUMORAL AND CELL-MEDIATED IMMUNE RESPONSE IN SHORT CHILDREN: EFFECT OF THERAPY WITH hGH

In 18 short children treated with hGH we investigated the ability of this hormone to influence the serum levels of immunoglobulins, in vitro IgM production, mitogen-stimulated lymphoproliferation, Sm-C and serum growth-promoting activity (Thymidine Activity, TA). Blood was collected before treatment (Gr. A), then on the 5th day following a 4 day course of daily hGH (0.1 U/kg) i.m. injections (Gr. B), then again after a 3 month course of hGH three times weekly (Gr. C). Lymphocytes were separated by centrifugation of Ficoll-Isopaque. The IgM production from the patients' unstimulated lymphocytes in vitro decreased from 277±41 (Gr. A), to 168±38 (Gr. B) and 119±43 ng/ml (Gr. C) (p 0.05). Using stimulated lymphocytes it decreased from 2015±464 (Gr. A) to 116±316 (Gr. B) and then to 511±170 ng/ml (Gr. C) (p 0.02). The variation of this decrease is correlated with the variation of growth velocity during treatment (r = 0.619, p 0.05), In contrast no significant changes were found following therapy neither in the serum levels of IgA, IgE, IgG, IgM, Sm-C and TA, nor in PHA, ConA and PWM-stimulated lymphoproliferation. Our data suggest some relationship between growth hormone, growth and immunity.