rhIGF-I Administration Research Articles

Potential applications for rhIGF-I: Bone disease and IGF[sbnd

Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6–10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I.

Treatment of growth failure in the absence of GH signaling: The Ecuadorian experience

Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment studies of growth failure in absence of growth hormone (GH) signaling (GH insensitivity -GHI, Laron syndrome -LS, GH Receptor deficiency -GHRD) have taken place in many locations around the globe. Results from these trials are comparable, and slight differences reported can be attributed to specific circumstances at different research sites.rhIGF-I treatment studies of GHI in Ecuador included various trials performed on children belonging to the largest and only homogeneous cohort of subjects with this condition in the world. All trials were performed by the same team of investigators and, during study periods, subjects received similar nutritional, physical activity and medical advice. Combination of these inherent conditions most likely creates less sources of variability during the research process. Indeed, diagnosis, selection and inclusion of research subjects; methodology used; transport, storage and delivery of study drug; data collection, monitoring and auditing; data analysis, discussion of results, conclusion inferences and reporting, etc., were submitted to the same sources of error.For the above-mentioned reasons, we are hereby mainly covering conclusions derived from rhIGF-I treatment studies of Ecuadorian children whit GHRD due to homozygosity of a splice site mutation occurring at GHR gene, whose unaffected parents were both heterozygous for the same mutation. We also describe studies of rhIGF-I administration in adolescent and adult subjects with GHRD, from the same cohort and with the same genetic anomaly.

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I

ObjectiveThis study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. DesignThe study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. ResultsPEGylation resulted in long exposure to RO5046013 with a half-life of 140–200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. ConclusionsPEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.

IGFALS Gene Dosage Effects on Serum IGF-I and Glucose Metabolism, Body Composition, Bone Growth in Length and Width, and the Pharmacokinetics of Recombinant Human IGF-I Administration

Acid labile subunit (ALS) deficiency, caused by IGFALS mutations, is a subtype of primary IGF-I deficiency (PIGFD) and has been associated with insulin resistance (IR) and osteopenia. Whether patients respond to recombinant human IGF-I (rhIGF-I) is unknown. This study determined the 14-hour pharmacokinetic response of free and total IGF-I and IGF binding protein 3 (IGFBP-3) to a single sc dose of rhIGF-I (120 μg/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting blood levels, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and metacarpal radiogrammetry were performed in the four patients and 12 heterozygous family members. IGF-I and IGFBP-3 increased above baseline (P < .05) for 2.5 hours, returning to baseline 7 hours after rhIGF-I injection. Mean (SD) IGF-I Z-score increased by 2.49 (0.90), whereas IGFBP-3 Z-score increased by 0.57 (0.10) only. IGF-I elimination rates in ALS deficiency were similar, but the IGF-I increment was lower than those for severe PIGFD. Significant gene dosage effects were found for all IGF-I peptides, height, forearm muscle size, and metacarpal width. Bone analysis showed that ALS deficiency creates a phenotype of slender bones with normal size-corrected density. Abnormal glucose handling and IR was found in three of four patients and 6 of 12 carriers. These gene dosage effects demonstrate that one functional IGFALS allele is insufficient to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination compared with severe PIGFD, ALS-deficient patients cannot mount a similar response. Alternative ways of rhIGF-I administration should be sought.

Renal tubular dysfunction in patients with molecular defects of the insulin receptor gene

To the editor, We readwith interest on a case of Donohue syndromewith renal tubular dysfunction (RTD) and amutation in the insulin receptor gene (INSR) written byHovnik et al. that was published recently in your journal [3]. The authors showed that although recombinant human insulin-like growth factor I (rh-IGF-I) therapy improved RTD, it did not improve the anabolic status of their patient. We recently reported on a case of Rabson–Mendenhall syndrome with INSR mutations and RTD [1]. Although the patient underwent rh-IGF-I therapy at the age of 4 months, his physical constitution continued to deteriorate, and RTD did not resolve. The therapeutic effect of rh-IGF-I varies between cases.We suggest that rh-IGF-I may have had an inadequate effect in the patient of the study of Hovnik et al. because anabolic status did not improve. Chin et al. showed that activation of phosphatidylinositol3-kinase (PI3K) stimulated endocytosis of the renal outer medullary potassium channel (ROMK) [2]. Insulin and IGFI can activate PI3K and therefore may inhibit renal potassium excretion by reducing the abundance of ROMK. However, our patient showed sustained RTD after administration of rhIGF-I, probably due to a poor response to rh-IGF-I. The patient in the study of Hovnik et al. appeared to be in a similar situation to our patient, because rh-IGF-I therapy did not improve their anabolic status. Therefore, recovery of RTD in their patient could not be fully explained by the effect of rhIGF-I. In our patient, RTD resolved spontaneously at the age of 18 months. The recovery of renal tubular function in Hovnik’s patient may have depended partially on rh-IGF-I treatment, although this may not have been the only mechanism. Some renal pathways other than the system mediated by IGF-I develop during infancy and may play a specific role in renal tubular function in patients with insulin receptor insufficiency.

Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats

ObjectiveAdjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and −5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats. DesignArthritis was induced in adult male Wistar rats by an intradermal injection of 4mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300μg/kg of rhGH or 200μg/kg of rhIGF or saline was administrated 18 and 3h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot. ResultsArthritis decreased serum IGF-I and IGF mRNA in liver (P<0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P<0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P<0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats. ConclusionsShort-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle.

Short-Term Administration of a Combination of Recombinant Growth Hormone and Insulin-Like Growth Factor-I Induces Anabolism in Maintenance Hemodialysis

Resistance to GH and IGF-I is a significant complication of severe chronic kidney disease, which contributes to muscle wasting. Pharmacological doses of recombinant human (rh) GH or rhIGF-I have been proposed to treat this catabolic condition. This study was undertaken to examine the potential additive anabolic effects of rhGH + rhIGF-I compared with rhIGF-I. We studied eight well-nourished hemodialysis patients in a random crossover design and compared the metabolic effects of a 3-d administration of moderate dose of rhIGF-I (40 microg/kg per 12h) with an association of rhIGF-I + rhGH (50 microg/kg/d). Leucine kinetics, plasma amino acids (AAs), serum insulin, and IGF binding proteins (IGFBP)-1 and -3 were measured. The net protein balance was not affected by rhIGF-I alone, whereas serum insulin and IGFBP-3 decreased (P < 0.05) and IGFBP-1 increased (P < 0.01). With the combination rhGH + rhIGF-I, an increase of IGFBP-3 (P < 0.01) and insulin (P < 0.01) as well as a decrease of IGFBP-1 (P < 0.01) occurred. Plasma essential AAs (P = 0.01) as well as the essential to nonessential AA ratio (P < 0.001) decreased. Whole-body protein net balance increased significantly (P < 0.05) with a 22% decrease in leucine oxidation and a 15% increase in nonoxidative leucine disposal. In dialysis patients, rhIGF-I administration at a moderate dose has no protein metabolic effect, but the association with a moderate dose of rhGH is followed by a significant anabolic response.

Immunological effects of insulin-like growth factor-I--enhancement of immunoglobulin synthesis.

In addition to its activity as a metabolic hormone and a regulator of somatic growth, insulin-like growth factor-I (IGF-I) has cytokine-like activities on lymphoid cells. A 14-day infusion of recombinant human (rh)IGF-I increased lymphocyte numbers in all the peripheral lymphoid organs examined. This increase was apparent for up to 3 weeks following cessation of hormone treatment. A second administration of rhIGF-I, given when the lymphocyte numbers in the rhIGF-I-treated mice had returned to control values, resulted in similar increases in the peripheral T and B cell populations. This increase in lymphocyte numbers had functional significance, since rhIGF-I-treated mice produced elevated antibody titres following primary or secondary antigen challenge compared with controls. In addition, when rhIGF-I-treated mice were immunized with a suboptimal dose of antigen they produced antibody titres which were equivalent to those generated by immunization with optimal doses of antigen. When examined in vitro, addition of rhIGF-I alone to cultures of splenocytes from antigen-primed mice stimulated immunoglobulin synthesis. These studies suggest that IGF-I produced locally by thymic and bone marrow stromal cells may be a natural component of B and T cell lymphopoiesis.

Insulin-like Growth Factor-I (rhIGF-I) Therapy of Short Stature

The United States Food and Drug Administration (FDA) approved the use of subcutaneously injected rhIGF-I in late 2005 for treatment of children with severe short stature from growth hormone (GH) insensitivity due to genetic defects in the GH receptor or postreceptor mechanisms or from the development of GH inactivating antibodies. The approval was based on 15 years experience treating these rare conditions with rhIGF-I. Because of the very small numbers of children with these conditions, there has been an effort to justify and promote broader use for rhIGF-I. Attempts to identify GH unresponsiveness in children with idiopathic short stature (ISS) have yielded only a handful of patients with rare genetic disorders. IGF-I treatment for unequivocal GH insensitivity improves but does not correct growth failure, in contrast to the typical experience with GH replacement of GH deficiency. This emphasizes the importance of direct effects of GH at the growth plate, including the stimulation of maturation of cartilage precursor cells and local production of IGF-I, effects that cannot be duplicated by exogenous administration of rhIGF-I. Adverse effects testify to the more than adequate delivery of administered rhIGF-I to other tissues; these include lymphoid hyperplasia, coarsening of the facies, and increased percentage body fat. The absence of convincing evidence of GH insensitivity in a substantial number of children with ISS, the limited ability of endocrine IGF-I to restore normal growth in those with unequivocal GH unresponsiveness, the suppression of endogenous GH (and thereby, local GH effects on growth) that occurs with IGF-I administration, the risk profile, and the absence of data on efficacy in other than proven severe GH insensitivity, led the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society to conclude that rhIGF-I use is only justified in conditions approved by the FDA and that other growth promotional use should only be investigational. Nonetheless, substantial numbers of children are being treated with rhIGF-I off-label, exuberant estimates of potentially eligible patients are projected, and several uncontrolled clinical trials have been undertaken which are not based on sound preliminary data or established growth principles, and a single four-arm study begun comparing monotherapy with rhGH to combination rhGH with three dosages of rhIGF-I as a single daily injection, a means of administration of rhIGF-I that has not been tested.

The Role of Recombinant Human Insulin-Like Growth Factor-I in Treating Children with Short Stature

Recombinant human (rh) IGF-I is now available to treat children with short stature resulting from severe primary IGF-I deficiency. This review from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society discusses different aspects of rhIGF-I therapy, particularly with regard to potential advantages and disadvantages in comparison with the traditional use of rhGH for treatment of short stature. We used the Entrez-PubMed search engine to conduct a review of publications addressing IGF-I deficiency, the use of rhIGF-I, and treatment for short stature. rhIGF-I, as a twice-daily sc injection, is now approved for treatment of short stature in children with severe primary IGF-I deficiency, which may occur as a consequence of mutations in the GH receptor, defects in the post-GH receptor signaling pathway, and IGF-I gene defects. It is also approved for children with GH deficiency who develop neutralizing antibodies to GH. rhIGF-I significantly improves growth in these conditions. However, adult height may still be suboptimal, possibly due to lack of direct GH effects. Dosing regimens for rhIGF-I administration are under investigation, as are other indications for use of rhIGF-I. The use of rhIGF-I is justified in conditions approved by the Food and Drug Administration. Until more substantial data become available, the use of rhIGF-I outside Food and Drug Administration recommendations should only be investigational.

Mecasermin rinfabate for severe insulin-like growth factor-I deficiency

Recombinant human insulin-like growth factor (rhIGF)-I has been shown to increase growth velocity in children with IGF-I deficiency, either as a result of growth hormone-insensitivity syndrome or IGF-I gene deletion (one case study). There have been adverse events, particularly hypoglycemia, reported with administration of unbound rhIGF-I. In addition, the serum half-life of unbound rhIGF-I is shorter when administered to patients with growth hormone-insensitivity syndrome, who have low serum concentrations of its binding proteins IGFBP-3 and acid-labile subunit, than when administered to normal volunteers or to patients with an IGF-I gene deletion (who had normal levels of IGFBP-3). Mecasermin rinfabate, an equimolar mixture of rhIGF-I and the recombinant form of its principal binding protein rhIGFBP-3 (rhIGF-I/rhIGFBP-3), was developed to prolong the half-life and to reduce the risk of acute adverse events (particularly hypoglycemia) associated with administration of rhIGF-I. Published data demonstrate ...

Efficacy and safety of mecasermin rinfabate

There has been interest in using recombinant human (rh) insulin-like growth factor (IGF)-I (rhIGF-I) to treat short stature, either alone or in combination with its binding protein (insulin-like growth factor binding protein [IGFBP]-3). IGF-I has been shown to increase growth velocity in children with IGF deficiency, either as a result of growth hormone insensitivity syndrome (GHIS) or IGF gene deletion. However, there have been adverse events, particularly hypoglycaemia, reported with administration of unbound rhIGF-I. In addition, the serum half-life of unbound rhIGF-I is shorter when administered to patients with GHIS, who have low serum concentrations of its binding proteins IGFBP-3 and acid-labile subunit (ALS), than when administered to normal volunteers or to the patient with an IGF-I gene deletion (who had normal levels of IGFBP-3). iPlex™ (mecasermin rinfabate), an equimolar mixture of IGF-I and its binding protein IGFBP-3, was developed to prolong the half-life and to counteract acute adverse events (particularly hypoglycaemia) associated with administration of IGF-I. Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders, it does appear that mecasermin rinfabate has a longer half-life in patients with GHIS than unbound IGF-I, and fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes.

Regulation of the splenic somatotropic axis by dietary protein and insulin-like growth factor-I in the rat.

Protein intake is a critical regulatory factor of the GH/IGF-I axis. Recently, it has been shown that splenic GH/IGF-I may respond to nutritional stress by preserving tissue homeostasis. To study the effects of exogenous administration of rhIGF-I on the splenic GH/IGF-I axis in protein malnourished rats, six-week-old male rats were assigned to one of four isocaloric diets differing in the protein content (0%, 4%, 12% and 20%) for a period of 12 days. Animals in the same dietary group on day 5 were randomly divided into two groups and during 7 days received a continuous subcutaneous infusion of either vehicle or rhIGF-I (300 microg/day). A low protein intake decreased the circulating levels of IGF-I, IGFBP-3, GH and insulin whereas the serum levels of IGFBP-1 were increased. Splenic IGFBP-3, -4 and -6 mRNA expression were up-regulated by protein malnutrition. Similarly, IGF-IR and GHR mRNA expression were significantly increased by the lack of dietary protein, whereas the levels of IGF-I mRNA remained unchanged. Exogenous rhIGF-I administration increased the circulating levels of IGFBP-1 and -3 in protein malnourished rats and reduced significantly the GH and insulin levels in well-fed rats. Similarly, rhIGF-I increased significantly the expression of the GHR in the spleen and splenic weight in all dietary groups, whereas nitrogen balance was enhanced only in the high-protein diet group. Among the cell subpopulations, B lymphocytes showed the highest GHR expression. These results suggest that in catabolic stress, induced by protein malnutrition the splenic GH/IGF-I axis is an important modulator and contributes to the maintenance of the homeostasis of the immune system.

Insulin-like growth factor I prevents corticosteroid-induced diaphragm muscle atrophy in emphysematous hamsters.

The aim of this study was to evaluate whether recombinant human insulin-like growth factor I (rhIGF-I) could attenuate or prevent diaphragm (DIA) fiber atrophy with corticosteroid (CS) administration to emphysematous (EMP) hamsters. DIA muscle IGF-I responses to CS administration with and without exogenous rhIGF-I administration were evaluated. Three groups were studied: 1) EMP; 2) EMP + triamcinolone (T; 0.4 mg.kg-1.day-1 im); and 3) EMP + T + IGF-I (600 microg/day by constant infusion). After 4 wk, the DIA was analyzed histochemically and biochemically (IGF-I mRNA levels by RT-PCR and endogenous and exogenous IGF-I peptide levels immunochemically). Body weights of EMP-T progressively decreased, while those of EMP and EMP-T-IGF-I remained stable despite similarly reduced food intake in both T groups. DIA weight was reduced with T but preserved with rhIGF-I infusion. DIA fiber proportions were similar among the groups. The cross-sectional areas of types I, IIa, and IIx fibers were reduced (17 to 31%) with T administration but unchanged with rhIGF-I infusion. DIA IGF-I mRNA levels were similar across all groups. By contrast, the endogenous DIA IGF-I levels were reduced (41%) in the EMP-T-IGF-I animals. Total DIA IGF-I levels (endogenous + exogenous) were still significantly reduced. IGF-I immunoreactivity confirmed this reduction in all DIA fibers. We conclude that DIA fiber atrophy with T was completely prevented by exogenous rhIGF-I administration. This effect was likely mediated by the pharmacological influences of exogenously administered rhIGF-I. We speculate that this results from increased bioavailability of free IGF-I to react with muscle receptors. Reduced endogenous IGF-I levels in the DIA likely reflect a negative-feedback influence. These results may have important clinical implications for treatment options to offset the adverse effects of CS on the respiratory muscles in patients with chronic lung disorders.

IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo.

IGF-I, a ubiquitous polypeptide, plays a key role in longitudinal bone growth and acquisition. The most predominant effect of skeletal IGF-I is acceleration of the differentiation program for osteoblasts. However, in vivo studies using recombinant human (rh) IGF-I and/or rhGH have demonstrated stimulation of both bone formation and resorption, thereby potentially limiting the usefulness of these peptides in the treatment of osteoporosis. In this study, we hypothesized that IGF-I modulates bone resorption by regulating expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) in bone cells. Using Northern analysis in ST2 cells, we found that human IGF-I suppressed OPG mRNA in a time- and dose-dependent manner: 100 micro g/LIGF-I (13 nM) decreased OPG expression by 37.0 +/- 1.8% (P < 0.002). The half maximal inhibitory dose of IGF-I was reached at 50 micro g/liter ( approximately 6.5 nM) with no effect of IGF-I on OPG message stability. Conditioned media from ST2 cells confirmed that IGF-I decreased secreted OPG, reducing levels by 42%, from 12.1-7 ng/ml at 48 h (P < 0.05). Similarly, IGF-I at 100 micro g/liter (13 nM) increased RANKL mRNA expression to 353 +/- 74% above untreated cells as assessed by real-time PCR. In vivo, low doses of rhGH when administered to elderly postmenopausal women only modestly raised serum IGF-I (to concentrations of 18-26 nM) and did not affect circulating OPG concentrations; however, administration of rhIGF-I (30 micro g/kg.d) for 1 yr to older women resulted in a significant increase in serum IGF-I (to concentrations of 39-45 nM) and a 20% reduction in serum OPG (P < 0.05). In summary, we conclude that IGF-I in a dose- and time-dependent manner regulates OPG and RANKL in vitro and in vivo. These data suggest IGF-I may act as a coupling factor in bone remodeling by activating both bone formation and bone resorption; the latter effect appears to be mediated through the OPG/RANKL system in bone.

Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects.

Severe gonadal androgen deficiency can have profound catabolic effects in man. Hypogonadal men develop a loss of lean body mass, increased adiposity, and decreased muscle strength despite normal GH and insulin-like growth factor I (IGF-I) concentrations. We designed these studies to investigate whether GH or IGF-I administration to male subjects with profound hypogonadism can diminish or abolish the catabolic effects of testosterone deficiency. Moreover, we also examined the nature of the interactions among GH, IGF-I, and androgens in specific genes of the im system. A group of 13 healthy subjects (mean age, 22 +/- 1 yr) was studied at baseline (D1) and 10 weeks after being made hypogonadal using a GnRH analog (GnRHa; D2). At 6 weeks from baseline they were started on either recombinant human (rh) IGF-I (60 microg/kg, sc, twice daily) or rhGH (12.5 microg/kg, sc, daily) for 4 weeks. On each study day subjects had infusions of L-[(13)C]leucine; indirect calorimetry; isokinetic dynamometry of the knee extensors; determination of body composition (dual energy x-ray absortiometry) and hormone and growth factor concentrations, as well as percutaneous muscle biopsies. Their data were compared with those of previously studied male subjects who received only GNRHA: Administration of rhIGF-I and rhGH to the hypogonadal men had similar effects on whole body metabolism, with maintenance of protein synthesis rates, fat oxidation rates, and fat-free mass compared with the eugonadal state, preventing the decline observed with hypogonadism alone. This was further amplified by the molecular assessment of important genes in muscle function. During rhIGF-I treatment, im expression of IGF-I declined, and IGF-binding protein-4 increased, similar to the changes during GnRHa alone. However, rhGH administration was associated with a marked increase in IGF-I and androgen receptor messenger ribonucleic acid concentrations in skeletal muscle with a reciprocal decline in IGF-binding protein-4 expression in the hypogonadal men. The gene expression for myostatin did not change. These effects were accompanied by a much greater increase in plasma IGF-I concentrations after rhIGF-I (225 +/- 32 vs. 768 +/- 117 microg/L) compared with the concentrations achieved during rhGH (217 +/- 20 vs. 450 +/- 19 microg/L). We conclude that 1) rhGH and rhIGF-I both may be beneficial in preserving lean body mass and sustaining rates of protein synthesis during states of severe androgen deficiency in man; 2) GH may affect the im IGF system via an a paracrine, local production of IGF-I; 3) androgens may be necessary for the full anabolic effect of GH/IGF-I in man. These hormones, particularly GH, may play a role in the treatment of hypogonadal men rendered hypogonadal pharmacologically or those unable to take full testosterone replacement. The latter requires further study.

Effect of IGF-I administration on growth hormone secretion in obese subjects.

The reduction of spontaneous and stimulated growth hormone (GH) secretion in obesity could reflect an increase of the inhibitory effect of insulin growth factor I (IGF-I) on somatotroph secretion. In the present study we aimed to verify the effect of low dose recombinant human IGF-I (20 microg/kg subcutaneously (s.c.) at 0 min) on 3 h-spontaneous GH secretion (mGHc, 0-180 min) and on the GH response to growth hormone releasing hormone (GHRH) (1 microg/kg i.v. at+180 min) in obesity. Five obese women with abdominal adiposity (OB, age, mean+/-s.e.m.: 31+/-7.13 y; BMI: 32.04+/-3.69 kg/m(2)) and eight age-matched lean women (NW, 28.3+/-1.2 y; 20.1+/-0.5 kg/m(2)) were studied. The mGHc and GHRH-induced GH response in OB (1.0+/-0.7 microg/l; AUC(180-270 min): 688.6+/-202.4 microg/l min, respectively) were lower than in NW (2.6+/-0.8 microg/l, 1315.9+/-189.9 microg/l min, respectively, P<0.05). The administration of rhIGF-I increased circulating IGF-I levels in OB and NW to the same extent (339.0+/-50.39 and 420.3+/-30.5 microg/l, respectively). The rhIGF-I administration did not affect mGHc in OB or NW (1.1+/-0.9 and 3.2+/-1.0 microg/l, respectively) but inhibited (P<0.05) the GH response to GHRH in OB (324.2+/-153.1 microg/l) and NW (730.2+/-288.1 microg/l). Our study shows that the administration of low dose rhIGF-I reduces the somatotroph responsiveness to GHRH in obesity as well as in normal subjects.

The effects of co-therapy with recombinant human insulin-like growth factor I and insulin on serum leptin levels in adolescents with type 1 diabetes mellitus

We previously demonstrated that in patients with type 1 diabetes mellitus (DM), co-therapy with subcutaneous (s.c.) recombinant human insulin-like growth factor I (rhIGF-I) and insulin improves glycemic control and reduces daily insulin requirements without inducing a significant change in body weight. However, it has been postulated that treatment with IGF-I may promote beneficial changes in body composition. Consequently, we assayed serum leptin, a peptide highly correlated with total fat mass, before and during chronic rhIGF-I administration. We studied 14 adolescents with type 1 DM (age range 12-19 yr). All patients were treated for 12 weeks with twice daily (BID) sc rhIGF-I in combination with standard BID split-mix insulin. At baseline, leptin concentrations were positively correlated with body mass index (BMI) (r(2) = 0.52, p = 0.004), as previously described for non-diabetic individuals. Leptin levels in diabetic females were higher than in diabetic males, and more than two times higher than in non-diabetic female controls. Baseline leptin levels did not correlate with patient age, duration of DM or hemoglobin A1c (HbA1c) measurements. The relationship between leptin concentrations and gender was maintained throughout treatment; however, average leptin levels did not change during 12 weeks of IGF-I + insulin co-therapy. These data suggest that despite treatment-induced improvements in HbA1c and serum IGF-I levels, serum leptin concentrations are unchanged by co-therapy with IGF-I + insulin. Moreover, these results suggest that improved metabolic control with IGF-I therapy is not obtained at the expense of increasing adiposity, a complication seen frequently with intensive insulin therapy.

Effects of Recombinant Human Insulin-Like Growth Factor I Administration on the Growth Hormone (GH) Response to GH-Releasing Hormone in Obesity1

Circulating GH levels are reduced in obesity due to true reduction of the 24-h GH production rate. GH insufficiency in obesity might reflect neuroendocrine abnormalities and/or alterations in peripheral hormones and metabolic factors. The somatotroph response to provocative stimuli including GHRH is markedly blunted in obese patients. However, the somatotroph responsiveness to GHRH in obesity shows also peculiar refractoriness to the inhibitory effect of glucose load. In this present study we aimed at verifying the effect of low dose rhIGF-I (20 microgram/kg, sc, at 0 min) on the GH response to GHRH (1 microgram/kg, iv, at 180 min) in obesity. With this goal in mind, six obese women with abdominal adiposity [OB; age (mean +/- SEM), 32.3 +/- 4.4 yr; body mass index, 32.8 +/- 2.3 kg/m(2)] were studied. The effects of recombinant human insulin-like growth factor I (rhIGF-I) administration on circulating total IGF-I, insulin, and glucose levels were also evaluated. The results in OB were compared with those recorded in age-matched lean women (NW; age, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m(2)), in whom the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I levels in OB were similar to those in NW (199.7 +/- 33.3 vs. 274.4 +/- 25.3 microgram/L). The mean GH concentration over 3 h (from 0-180 min) in OB was lower than that in NW (0.9 +/- 0.4 vs. 2.6 +/- 0.8 microgram/L; P = NS). Administration of GHRH induced a GH response in OB lower than that in NW (area under the curve from 180-270 min, 576.5 +/- 137.5 vs. 1315.9 +/- 189.9 microgram/L.min; P < 0.02). Administration of rhIGF-I increased circulating IGF-I levels in both groups to the same percent extent (326.8 +/- 28.3 and 420.3 +/- 26.5 microgram/L in OB and NW, respectively). rhIGF-I administration inhibited the GH response to GHRH in OB (240.1 +/- 99.6 microgram/L; P < 0.05) as well as in NW (730.2 +/- 288.1 microgram/L; P < 0.05), although it failed to lower the mean GH concentration over 3 h in either OB or NW. After rhIGF-I the GH response to GHRH in OB was slight and was still lower (P < 0.05) than that in NW; in fact, the percent decreases were similar in both groups (44.21 +/- 14.06 and 48.21 +/- 13.95 microgram/L, in OB and NW, respectively). The mean insulin (107.1 +/- 21.9 and 36.8 +/- 7.2 pmol/L), but not glucose (4.0 +/- 0.3 and 4.1 +/- 0.1 mmol/L), levels calculated over 270 min, were higher (P = 0.005) in OB than in NW; rhIGF-I administration did not modify insulin and glucose levels in either group. Our study shows that the sc administration of a low rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese as well as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect of rhIGF-I is preserved in obesity.

Effects of recombinant human insulin-like growth factor I administration on spontaneous and growth hormone (GH)-releasing hormone-stimulated GH secretion in anorexia nervosa.

Exaggerated GH and reduced insulin-like growth factor I (IGF-I) levels are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 +/- 0.6 kg/m2] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0 microg/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 microg/kg, sc) significantly reduced mGHc in AN (P < 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups; mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P < 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P < 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.