A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar growth hormone, in children with growth hormone deficiency

Valtropin is a recombinant human GH (rhGH) manufactured using a novel yeast expression system, classed as a 'biosimilar'. Valtropin was compared with Humatrope in children with GH deficiency (GHD). Treatment-naive, prepubertal children with GHD were randomized to Valtropin (n = 98) or Humatrope (n = 49) for 1 year. Standing height was measured 3-monthly and height velocity (HV) calculated. Serum IGF-I, IGFBP-3 and GH antibodies were determined centrally. HV at 1 year was 11.3 +/- 3.0 cm/year with Valtropin and 10.5 +/- 2.8 cm/year with Humatrope. Treatment difference was 0.09 cm/year with 95% confidence limits of -0.71, 0.90, within the preset non-inferiority limit of -2.0 cm/year. Height standard deviation (SD) scores were increased in both treatment arms with no acceleration of bone maturation. IGF-I and IGFBP-3 were increased comparably for both treatments. Adverse events showed no clinically relevant differences between treatment groups. Anti-GH antibodies were detected in 3 (3.1%) Valtropin and 1 (2.0%) Humatrope patients and the growth pattern was indistinguishable from the rest of the cohort. The 1-year efficacy and safety profile of Valtropin, a new biosimilar rhGH, are equivalent to the comparator rhGH, Humatrope. Valtropin can be used for the treatment of children with GHD and longer term data will fully establish its efficacy and safety profile.     

Comparison between short- and long-term insulin-like growth factor response to recombinant human growth hormone.

Eight growth-hormone-deficient children were treated with recombinant human GH (rhGH). Results of the short-term metabolic response to rhGH performed at the start of therapy during a 5-day introduction period and long-term results on growth were analyzed. We could not find any correlation between the effects on the short-term metabolic test and the growth response during long-term therapy, namely between the urea and insulin-like growth factor-I response during the short test and the increase in growth velocity. The short-term test is not a good predictor of the long-term response.     

Recombinant human insulin-like growth factor I (IGF-I): risks and benefits of normalizing blood IGF-I concentrations

Recombinant human (rh) insulin-like growth factor I (IGF-I) is being developed as a therapy for short stature caused by IGF deficiency (IGFD) and also for diabetes mellitus. To complement the human efficacy and safety data, a large amount of information is available regarding the pharmacology and toxicology of rhIGF-I in animals. This review summarizes the risks and benefits of normalizing blood IGF-I concentrations in IGFD, especially with regard to carcinogenicity, and compares and contrasts safety data for rhIGF-I, recombinant human growth hormone (rhGH), and insulin. A major difference between rhIGF-I and rhGH is that rhIGF-I (like insulin) has hypoglycaemic activity, whereas rhGH opposes insulin action and is diabetogenic. In most of their actions, GH and IGF-I are similar. IGF-I mediates most of the actions of GH, so the safety of rhGH and that of rhIGF-I also share many common features. In animals, the transgenic expression of hGH has been shown to act directly, by activating the prolactin receptor, to increase the incidence of mammary and prostate tumours. In comparison, the over-expression of IGF-I in animals or the administration of rhIGF-I does not have a carcinogenic effect. In formal toxicology and carcinogenicity studies, rhIGF-I has similar effects to insulin in that it can increase food intake, body size, and the growth rate of existing tumours. In animals and humans, IGFD has many long-term detrimental effects besides short stature: it increases the risk of diabetes, cardiovascular disease, and low bone mineral density. Therefore, a case can be made for replacement therapy with rhIGF-I to normalize blood IGF-I levels and reverse the detrimental effects of IGFD.     

Comparative study of biosynthetic human growth hormone immunogenicity in growth hormone deficient children

The immunogenicities of six recombinant human growth hormone (rhGH) preparations, from KABI (A rhGH191 and B rhGH192), Eli Lilly (C), Nordisk (D), Sanofi (E) and Serono (F), used to treat 260 GH-deficient children, have been compared using a common specific and sensitive procedure for antibody determination. For this purpose we developed two immunoassays: a competitive liquid radioimmunoassay using 125I-rhGH, and an immunometric solid enzymoimmunoassay in which the rhGHs were immobilized. Blood samples were collected from the GH-deficient children before treatment and after 3, 6, 9, 12, 18 and 24 months of therapy. Human GH antibodies were detected in children treated with 3 of the 6 rhGH preparations. Seven percent of the patients treated with hormone A, 14% with hormone B and 22% with hormone C formed antibodies against the respective rhGH. Differences in capacity and affinity of the hGH antibodies were observed between these anti-GH-positive groups. They could be divided into 2 groups according to their immunopotency. One group (7, 14 and 6% of the patients treated with hormones A, B and C, respectively) developed anti-hGH antibodies with very low binding capacities (30-100 fmol/ml). The other group (16% of the patients treated with hormone C) developed IgG-type antibodies to hGH with higher binding capacities (200-1,200 fmol/ml) and a measurable binding affinity (Ka = 10(8) M-1). These hGH antibodies partially inhibited the binding of labeled GH to its specific liver membrane receptor. However, because of their low titer, they did not inhibit growth in the treated children.(ABSTRACT TRUNCATED AT 250 WORDS)     

Body composition as a clinical endpoint in the treatment of growth hormone deficiency

Endpoints in the treatment and management of adults with growth hormone (GH) deficiency (GHD) can be problematic. Changes in body composition with recombinant human GH (rhGH) treatment may be one of the most objective measures that could be applied in judging the effectiveness and long-term efficacy. The relative strengths and weaknesses of measures of body composition and their potential for clinical utility in the setting of rhGH replacement in GHD in adults are discussed. Measurement of changes in body fat, regardless of the method employed, from pretreatment baseline through 2-6 months of treatment may be quite useful in demonstrating the efficacy of rhGH in each patient. Other changes in body composition are compromised by the imprecision of the measurements, shifts in extracellular water, and the small real changes which occur in bone and muscle in the GHD subject. Use of body composition measures of change in fat content as an endpoint in determining the efficacy of rhGH treatment in adults with GHD cannot be implemented on the basis of current data and would require a carefully designed prospective, controlled study. Until such criteria are established and accepted, endocrinologists must continue to manage these patients purely on the basis of their clinical judgment.     

Growth hormone treatment in short Japanese children born small for gestational age

Recent reports have shown that high-dose growth hormone (GH) treatment in short children born with small for gestational age (SGA) resulted in a pronounced acceleration of linear growth. We describe the results of multicenter trials of recombinant human GH (rhGH) treatment in short SGA children in Japan. Two clinical studies were performed and the results were combined. Study 1 comprised 104 SGA children and study 2 comprised 61 SGA children. The patients were divided into three groups: group 1 consisted of 20 patients (13 boys and 7 girls) who received rhGH 25 microg/kg per day six or seven times per week in the first year and 50 microg/kg per day in the second year and thereafter; group 2 consisted of 48 patients (28 boys, 20 girls) who received rhGH 45/50 microg/kg per day; group 3 consisted of 44 patients (28 boys, 16 girls) who received 90/100 microg/kg per day. The mean increments in height SDS were 0.46, 0.67 and 0.94 SD in boys and 0.49, 0.79 and 0.93 SD in girls in groups 1, 2 and 3, respectively. The mean increment in height SDS at 2 years in group 3 was significantly greater than that in group 1, but it was not significantly different from that in group 2 in boys and girls. Our data demonstrated that high-dose GH administration significantly improved height velocity and height SDS in short SGA children. Additional studies are necessary to optimize a long-term GH treatment regimen and combined luteinizing hormone releasing hormone analog treatment for final height. Careful observation is also necessary to assess the metabolic effects of high-dose GH, especially on carbohydrate metabolism.     

Final height in children with idiopathic growth hormone deficiency treated with a fixed dose of recombinant growth hormone

There is no consensus regarding the optimal dosing of recombinant human growth hormone (rhGH) for children with growth hormone deficiency (GHD). Our objective was to evaluate the final adult height (FAH) in children with idiopathic GHD treated with a fixed rhGH dose of 0.18 mg/kg/week. We reviewed all charts of patients with idiopathic GHD treated with rhGH since 1985 who reached FAH. Ninety-six patients were treated for an average of 5.4 years. The mean age was 11.9 years, the mean height -2.87 standard deviation score (SDS) and the mean FAH was -1.04 SDS. Females had a lower predicted adult height than males at the initiation of therapy (-2.0 vs. -1.01 SDS; p = 0.0087) but a higher FAH - predicted adult height (1.08 vs. 0.04 SDS; p = 0.0026). In multiple regression analysis, the FAH SDS was positively related to the midparental height SDS, the height SDS at GH initiation and growth velocity during the first year of therapy, and negatively correlated with peak GH and bone age at initiation (r(2) = 0.51; p < 0.005). Treatment of children with idiopathic GHD with a fixed dose of 0.18 mg/kg/week rhGH is sufficient to reach FAH within 2 SDS of the normal population range (84%) with an average FAH within -0.5 SDS of midparental height.     

Comparative proteomic analysis in children with idiopathic short stature (ISS) before and after short‐term recombinant human growth hormone (rhGH) therapy

This study was undertaken to identify growth hormone (GH) responsive proteins and protein expression patterns by short‐term recombinant human growth hormone (rhGH) therapy in patients with idiopathic short stature (ISS) using proteomic analysis. Seventeen children (14 males and three females) with ISS were included. They were treated with rhGH at a dose of 0.31 ± 0.078 mg/kg/week for 3 months. Immunodepletion of six highly‐abundant serum proteins followed by 2D DIGE analysis, and subsequent MALDI TOF MS, were employed to generate a panel of proteins differentially expressed after short‐term rhGH therapy and verify the differences in serum levels of specific proteins by rhGH therapy. Fourteen spots were differentially expressed after rhGH treatment. Among them, apo E and apo L‐1 expression were consistently enhanced, whereas serum amyloid A was reduced after rhGH therapy. The differential expressions of these proteins were subsequently verified by Western blot analysis using sera of the before and after rhGH treatment. This study suggests that rhGH therapy influences lipoprotein metabolism and enhances apo L‐1 protein expression in ISS patients.     

Response to long-term growth hormone therapy in short children with reduced GH bioactivity

BACKGROUND/AIMS: The aim of the present study was to investigate whether short children with normal growth hormone (GH) immunoreactivity, but reduced bioactivity (bioinactive GH) could benefit from rhGH treatment as GH deficient (GHD) patients. Methods: We evaluated 12 pre-pubertal children (8 M, 4 F), with GH deficiency-like phenotype showing normal serum GH peak levels (>10 ng/ml), measured by immunofluorimetric assay (IFMA-GH), in contrast with a reduced GH bioactivity (bio-GH), evaluated using the Nb(2) cells. We also evaluated 15 age-matched GHD pre-pubertal children (11 M, 4 F) with serum GH peak <5 ng/ml. Both groups were treated with rhGH therapy at the dose of 0.23 mg/kg/week s.c. RESULTS: Serum bio-GH/IFMA-GH ratio at peak time for each patient during the provocative test was significantly lower in bioinactive GH than in GHD children (0.29 vs. 2.05, p = 0.00001). Recombinant human GH therapy induced a significant (p < 0.001) increase in growth rate in both groups during the first 2 years. In the third year of treatment, while growth rate in GHD children is maintained, in bioinactive GH patients it decreases remaining, however higher compared to the pre-treatment one. CONCLUSIONS: Short rhGH therapy given to selected bioinactive GH children improve growth rate and might result in greater final adult height.     

Growth hormone therapy in short children born small for gestational age

There is still a lack of data from randomized, controlled, long-term studies of growth hormone (GH) treatment in children born small for gestational age (SGA), but the available evidence indicates consistently that GH therapy is a valid growth-promoting treatment in these children, particularly if started early. Whilst side effects appear uncommon, ongoing surveillance is required and treated children should be monitored for changes in glucose homeostasis, lipid profiles and blood pressure, especially during puberty. We provide an update on the safety and efficacy of GH treatment in short children born SGA.     

Excipient exchange in the comparison of preparations of the same biologic made by different manufacturing processes: An exploratory study with recombinant human growth hormone (rhGH)

Demonstrations of bio-similarity between subsequent entry (follow-on) biologics and innovator’s formulated drug products may depend upon methods that either remove excipients completely or allow the exchange of excipients to give equivalent formulations. Excipient exchange through dialysis is perhaps the simplest of such methods but its use has been hotly debated. This debate, in the absence of published data, has relied largely on theoretical considerations. This study presents data that indicate that excipient exchange can allow comparisons of different formulations of the same therapeutic protein. The use of excipient exchange to and from one concentration of mannitol to another or to a mixture of glycine and mannitol was reproducibly demonstrated for recombinant human growth hormone (rhGH). We show that marketed rhGH products from several different manufacturers exhibit differences in conformational stability when compared directly. These differences, however, are shown to be the result of differences in formulation rather than in the drug substance itself and were removed through excipient exchange. The data presented, therefore, also indicate that failure to assure a common excipient background can lead to erroneous conclusions about the similarities and differences in the physico-chemical properties of two preparations of the same therapeutic protein made by different manufacturing processes.     

The challenge of indication extrapolation for infliximab biosimilars

A biosimilar is intended to be highly similar to a reference biologic such that any differences in quality attributes (i.e., molecular characteristics) do not affect safety or efficacy. Achieving this benchmark for biologics, especially large glycoproteins such as monoclonal antibodies, is challenging given their complex structure and manufacturing. Regulatory guidance on biosimilars issued by the U.S. Food and Drug Administration, Health Canada and European Medicines Agency indicates that, in addition to a demonstration of a high degree of similarity in quality attributes, a reduced number of nonclinical and clinical comparative studies can be sufficient for approval. Following a tiered approach, clinical studies are required to address concerns about possible clinically significant differences that remain after laboratory and nonclinical evaluations. Consequently, a critical question arises: can clinical studies that satisfy concerns regarding safety and efficacy in one condition support “indication extrapolation” to other conditions? This question will be addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through extrapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions.     

Purification of recombinant growth hormone by clear native gels for conformational analyses: preservation of conformation and receptor binding

Most protein preparations require purification steps prior to biophysical analysis assessing protein stability, secondary structure and degree of folding. It was, therefore, the aim of this study to develop a system to separate and purify a protein from a commercially available medicinal product, recombinant human growth hormone (rhGH) and show preservation of conformation and function following the gel-based procedure. The rhGH was run on clear native (CN) gels and recovered from the gels by electroelution using D-Tube Dialyzer Midi under rigorous cooling. Melting point studies indicated preservation of the structural integrity. This finding was confirmed by synchrotron radiation circular dichroism spectroscopy (SRCD) revealing an identical folding pattern for the sample before and after electrophoretic separation and purification. Synchrotron small-angle X-ray scattering (SAXS) indicated that the sample was folded and monomeric, both before and after separation and purification, and that its shape corresponded well to the known crystal structure of GH. Binding properties of rhGH to a receptor-model system before and after clear native electrophoresis were comparable. This analytical and preparative approach to purify and concentrate a protein preserving conformation and function may be helpful for many applications in analytical, protein and stereochemistry.     

Biosimilars: a regulatory perspective from America

Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product. This paper reviews the processes for approval of biosimilars in the US and the European Union and highlights recent changes in federal regulations governing the approval of biosimilars in the US.     

Recombinant therapeutic proteins: production platforms and challenges

Since the approval of insulin in 1982, more than 120 recombinant drug substances have been approved and become available as extremely valuable therapeutic options. Exact copying of the most common human form is no longer a value per se, as challenges, primarily related to the pharmacokinetics of artificial recombinant drugs, can be overcome by diverging from the original. However, relatively minor changes in manufacturing or packaging may impact safety of therapeutic proteins. A major achievement is the development of recombinant proteins capable of entering a cell. Such drugs open up completely new opportunities by targeting intracellular mechanisms or by substituting intracellularly operating enzymes. Concerns that protein variants would cause an intolerable immune response turned out to be exaggerated. Although most recombinant drugs provoke some immune response, they are still well tolerated. This knowledge might result in a change in attitude towards antibody formation, i.e., neutralizing antibody activity (in vitro) may be overcome by dosing consistently on the basis of antibody titers and not only on body weight. As with other drugs, efficacy and safety of therapeutic proteins have to be demonstrated in clinical studies, and superiority over available products has to be proven instead of just claimed.     

Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength

The effect of recombinant DNA human growth hormone (rhGH) treatment in adults with growth hormone (GH) deficiency was studied in 24 patients in a double-blind placebo-controlled trial. The dose was 0.07 U/kg body wt daily. After 6 mo of treatment, significant increases were noted in the rhGH group for total cross-sectional area of thigh muscle (+11.2 +/- 3.1 vs. -0.5 +/- 3.0 cm2; P = 0.015 vs. placebo) and quadriceps muscle (+4.1 +/- 0.8 vs. +0.4 +/- 1.2 cm2; P = 0.031) measured by computerized tomography. Strong correlations were noted between lean body mass (measured as total body potassium) and total thigh muscle area in normal and GH-deficient adults both before and after rhGH treatment. Strength of hip flexors (+1.25 +/- 0.27 vs. +0.25 +/- 0.12 z-scores; P = 0.004) and limb girdle muscles increased (P = 0.02) in the rhGH group. We conclude that 1) rhGH increases lean tissue and skeletal muscle mass in adults with human GH deficiency, 2) this suggests a role for GH in the regulation of body composition of adult humans, 3) the increase in strength of limb girdle muscles after rhGH treatment suggests that adults with GH deficiency may have a proximal myopathy, and 4) the failure to demonstrate an increase in strength in other muscle groups may require the study of larger numbers of patients.     

American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Growth Hormone Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG).Methods: Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.Results: The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence).Conclusion: This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH–stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document.LAY ABSTRACTThis updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH–stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH–stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH–stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement.Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AHSG = alpha-2-HS-glycoprotein; AO-GHD = adult-onset growth hormone deficiency; ARG = arginine; BEL = best evidence level; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CO-GHD = childhood-onset growth hormone deficiency; CPG = clinical practice guideline; CRP = C-reactive protein; DM = diabetes mellitus; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = Food and Drug Administration; FD-GST = fixed-dose glucagon stimulation test; GeNeSIS = Genetics and Neuroendocrinology of Short Stature International Study; GH = growth hormone; GHD = growth hormone deficiency; GHRH = growth hormone–releasing hormone; GST = glucagon stimulation test; HDL = high-density lipoprotein; HypoCCS = Hypopituitary Control and Complications Study; IGF-1 = insulin-like growth factor-1; IGFBP = insulin-like growth factor–binding protein; IGHD = isolated growth hormone deficiency; ITT = insulin tolerance test; KIMS = Kabi International Metabolic Surveillance; LAGH = long-acting growth hormone; LDL = low-density lipoprotein; LIF = leukemia inhibitory factor; MPHD = multiple pituitary hormone deficiencies; MRI = magnetic resonance imaging; P-III-NP = procollagen type-III amino-terminal pro-peptide; PHD = pituitary hormone deficiencies; QoL = quality of life; rhGH = recombinant human growth hormone; ROC = receiver operating characteristic; RR = relative risk; SAH = subarachnoid hemorrhage; SDS = standard deviation score; SIR = standardized incidence ratio; SN = secondary neoplasms; T3 = triiodothyronine; TBI = traumatic brain injury; VDBP = vitamin D-binding protein; WADA = World Anti-Doping Agency; WB-GST = weight-based glucagon stimulation test     

Effects of recombinant human growth hormone on height and skeletal maturation in growth hormone-deficient children with and without severe pretreatment bone age delay

The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. METHODS: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score 相似文献   

Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance

Growth hormone (GH) treatment in adults with GH deficiency increases lean body mass and thigh muscle cross-sectional area. The functional significance of this was examined by incremental cycle ergometry in 24 GH-deficient adults treated in a double-blind placebo-controlled trial with recombinant DNA human GH (rhGH) for 6 mo (0.07 U/kg body wt daily). Compared with placebo, the rhGH group increased mean maximal O2 uptake (VO2max) (+406 +/- 71 vs. +133 +/- 84 ml/min; P = 0.016) and maximal power output (+24.6 +/- 4.3 vs. +9.7 +/- 4.8 W; P = 0.047), without differences in maximal heart rate or ventilation. Forced expiratory volume in 1 s, vital capacity, and corrected CO gas transfer were within normal limits and did not change with treatment. Mean predicted VO2max, based on height and age, increased from 78.9 to 96.0% in the rhGH group (compared with 78.5 and 85.0% for placebo; P = 0.036). The anaerobic ventilatory threshold increased in the rhGH group (+159 +/- 39 vs. +1 +/- 51 ml/min; P = 0.02). The improvement in VO2max was noted when expressed per kilogram body weight but not lean body mass or thigh muscle area. We conclude that rhGH treatment in adults with GH deficiency improves and normalizes maximal exercise performance and improves submaximal exercise performance and that these changes are related to increases in lean body mass and muscle mass. Improved cardiac output may also contribute to the effect of rhGH on exercise performance.