Decreased serum levels of insulin-like growth factors and IGF binding protein 3 in osteoporosis

Abstract. Objectives. The aim of the study was to investigate endogenous growth hormone (GH) secretion in patients with osteoporosis and in patients with degenerative bone diseases or no spinal disease by measuring serum insulin-like growth factors 1 and 2 (IGFs) and their major binding protein 3 (BP-3) as an indirect parameter of GH secretion. Design. A cross-sectional study. Setting. All patients were seen as out-patients of the Endocrinology Department of the University of Heidelberg where all bone parameters were measured. IGFs and BP-3 serum levels were measured at the Children's Hospital of the University of Tübingen. Subjects. A total number of 310 patients were studied. The group with primary osteoporosis and vertebral fractures (OPO) consisted of 141 patients (98 females, 43 males). Spinal degenerative bone disease or osteoarthritis (DEG) was present in 108 patients (91 females, 17 males). Sixty-one control patients (56 females, 5 males) had no spinal disease on X-ray, but presented with lower back pain. Main outcome measures. Serum levels of IGFs, BP-3, PTH and 25-vitamin D₃ were measured by radioimmunoassay. Bone mineral density (BMD) was determined using absorptiometry; anthropometric parameters and menopausal status were recorded. Results. There was no difference in age and years after menopause between OPO and DEG, but control individuals were younger. Mean IGFs and BP-3 serum levels in patients with OPO were lower (P < 0.001) than those in patients with DEG or in controls. Patients with DEG had significantly higher BP-3 levels than controls (P < 0.001). There was a significant (P < 0.05) negative correlation of BP-3 with age in females with OPO, but not in controls or in DEG patients. The IGFs did not decrease with age in any of the three groups. Binding protein 3 was positively correlated (P < 0.05) with BMD in postmenopausal women with OPO but not in controls or DEG patients. Conclusion. We conclude that systemic IGFs and IGF binding protein 3 are decreased in patients with osteoporosis. Further studies are needed to investigate whether this is as a result of diminished secretion of endogenous GH and whether this reflects the local circumstances of IGFs and IGF binding proteins in bone.     

Diurnal variation in serum insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations during daily subcutaneous injections of recombinant human growth hormone in GH-deficient adults

OBJECTIVE  Whereas there seems to be little, if any, circadian variation in circulating concentrations of IGF-I and IGFBP-3 in healthy subjects, there are conflicting reports on this issue in GH-deficient patients treated with GH as a daily subcutaneous injection. We have therefore investigated the 24-hour serum profiles of IGF-I and IGFBP-3 concentrations after one week and more than one year of GH treatment.
PATIENTS  Eleven subjects, with adult onset GH deficiency mainly caused by pituitary adenomas were included in the study.
DESIGN AND MEASUREMENTS  In an open study, six subjects (three women and three men; age (±SEM) 41.2±3.9 years) were investigated after one week of GH therapy and five subjects (three women and two men; age (±SEM) 61.4±3.3 years) were investigated after 13–40 months of GH therapy. The GH injections were given at 2000 h. The subjects were hospitalized for 24-hour blood sampling at 1-hour intervals and serum concentrations of GH, IGF-I and IGFBP-3 were determined.
RESULTS  There was a significant diurnal variation in serum IGF-I and IGFBP-3 concentrations both in the subjects who had received GH for one week and in those who had received GH treatment for more than one year. The serum concentrations of IGF-I and IGFBP-3 were highest in the morning and lowest during night-time and early morning. The molar IGF-I/IGFBP-3 ratio varied significantly with time in both groups of patients in a similar way as IGF-I and IGFBP-3 indicating a more pronounced variation in IGF-I compared with IGFBP-3 in response to the GH therapy.
CONCLUSION  Significant diurnal variations in serum IGF-I and IGFBP-3 concentrations occur after one week and more than one year of GH treatment with daily subcutaneous injections. The results indicate that the free fraction of IGF-I may exhibit a diurnal variation.     

Increased orderliness of growth hormone (GH) secretion in GH-deficient adults with low serum insulin-like growth factor I

Available studies suggest that a proportion of GH-deficient (GHD) adults maintain serum IGF-I concentrations within the age- and sex-matched normal range. The basis for this distinction is not known. In this study 24-h GH profiles (sampling every 30 min) were appraised in five GHD adults with low serum IGF-I concentrations (<2 SD of the age- and sex-matched normal range), five GHD adults with normal serum IGF-I levels (within +/-2 SD), and five healthy subjects. Serial GH concentrations, measured using a chemiluminescence assay, were analyzed by deconvolution and approximate entropy (ApEn; regularity) analyses. The apparent half-duration of GH secretory bursts was longer in both GHD groups than in the healthy controls, as determined by deconvolution analysis (P < 0.05 each). The GH burst frequency was higher, the interburst interval was shorter, and the GH burst amplitude was lower in GHD adults with normal serum IGF-I than in healthy controls (P < 0.05, P < 0.05, and P < 0.01, respectively). The percentage of total daily GH secretion that was pulsatile was also reduced in the GHD adults with normal serum IGF-I compared with the other two groups (P < 0.05 and P < 0.05, respectively). In contrast, ApEn ratios were lower in the GHD adults with low serum IGF-I than in the GHD adults with normal IGF-I and controls (P < 0.01 and P < 0.05, respectively). Serum IGF-I concentrations correlated positively with ApEn ratios in the total study population (n = 15) and in the GHD adults (n = 10). In conclusion, 24-h patterns of GH release differed in GHD adults with low vs. normal serum IGF-I concentrations. GHD adults with low IGF-I levels maintain low ApEn ratios (denoting greater relative orderliness of GH secretion), whereas GHD patients with normal IGF-I values generate a high frequency, low amplitude GH output. The foregoing contrasts point to distinct neuroendocrine features of the GH-deficient state of adults, which can be related to concurrent IGF-I production.     

Pulsatile versus continuous intravenous administration of growth hormone (GH) in GH-deficient patients: effects on circulating insulin-like growth factor-I and metabolic indices

The episodic and pulsatile nature of GH secretion in normal man is well established. Studies in hypophysectomized rats have indicated that pulsatile administration of GH is superior to continuous infusion in promoting growth, but similar studies have not yet been conducted in human subjects. We compared three different iv GH administration schedules in six GH-deficient patients. They were hospitalized three times for 44 h on three occasions, separated by at least 4 weeks without GH treatment. On each occasion they received 2 IU GH, administered iv as either 1) two boluses (at 2000 and 0200 h), 2) eight boluses (at 3-h intervals starting at 2000 h), or 3) a continuous (2000-0200 h) infusion. Serum insulin-like growth factor-I (IGF-I) after eight boluses and that after continuous infusion were almost identical, with a steep increase reaching a peak at 2000-2400 h, followed by a steady decline. The total areas under the curve, expressed as mean levels (micrograms per L), were 147.6 +/- 11.8 (eight boluses) and 151.2 +/- 8.9 (infusion; P = NS). The change with time in IGF-I after the two-bolus regimen differed significantly from that in the other studies (P less than 0.001), displaying only a modest increase, as also reflected in a smaller area under the curve of serum IGF-I (125.3 +/- 8.7 micrograms/L; P less than 0.05). No differences in blood glucose, serum insulin, or plasma glucagon were observed when comparing the three studies. Both blood glucose and serum insulin tended to be elevated during the second night of each study. Almost identical fluctuations were recorded in lipid intermediates in the three studies, with nightly elevations being more pronounced on the first night. Alanine and lactate exhibited nearly identical patterns in the three studies and were characterized by low nocturnal levels. These data indicate that small but frequent iv boluses and continuous infusion of GH are equally effective in generating an increase in IGF-I in GH-deficient patients, whereas the same amount of GH given as two large boluses results in a significantly smaller increase in IGF-I. This could mean that a prolongation of the period during which serum GH is above zero in GH-treated subjects is just as essential as pulsatility for the growth-promoting effects of the hormone.     

Circadian patterns of serum insulin-like growth factor (IGF) II and IGF binding protein 3 in growth hormone-deficient patients and age- and sex-matched normal subjects.

Knowledge of the circadian patterns of serum IGF-II and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 1U) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553 +/- 78 (evening GH), 554 +/- 54 (morning GH), and 429 +/- 65 micrograms/l (no GH). The mean IGF-II level in the normal subjects was 635 +/- 29 micrograms/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853 +/- 301 (no GH), 2755 +/- 317 (evening GH), 2904 +/- 269 (morning GH), and 3856 +/- 186 micrograms/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of human growth hormone therapy on GH binding protein in GH-deficient children

Previous studies have described the close similarity of the GH binding protein to the liver membrane GH receptor. Since GH regulates its own liver receptors, we examined the effects of short- and long-term hGH therapy on GH binding protein in children with GH deficiency. Six GH-deficient children received their first hGH dose ever, and the pharmacodynamics of serum GH was followed for 12 h, along with measurements of GH binding protein activity. Over the first 6 h, serum GH and GH binding protein activity exhibited a parallel increase, followed by gradual decrease. At 8 h, some of the patients exhibited an apparent second peak in GH binding protein, despite the continuous decrease in serum hGH. During the period of hGH treatment, serum GH binding protein increased progressively over a period of 6 months. In a second uncontrolled group of 7 GH-deficient patients who had been treated with hGH for 30-36 months, GH binding protein activity was also significantly higher than pretreatment values. We suggest that the short-term pharmacodynamic changes probably represent the endogenous turnover of the GH receptor, whereas the elevated GH binding protein activity on hGH treatment may reflect up-regulation of the GH receptor.     

Corticoid-induced growth hormone (GH) secretion in GH-deficient and normal children.

Acute administration of corticoids is a potent stimulus of GH secretion in man. To ascertain their mechanism and point of action as well as the suitability of this novel test in the diagnosis of GH-deficient states, normal controls and GH-deficient children were studied. They were selected based on auxological criteria and the GH response to provocative stimuli. The GH-deficient children presented a blunted GH (mean +/- SEM; microgram/L) discharge after insulin-induced hypoglycemia (2.9 +/- 0.4), propranolol-exercise (7.4 +/- 1.5), and clonidine (6.5 +/- 0.8) compared with values in the normal children (7.2 +/- 2.2, 15.8 +/- 2.4, and 15.6 +/- 1.8, respectively). As expected, GH-releasing hormone (GHRH)-induced GH discharge in GH-deficient children (33.2 +/- 4.9) was similar to that in the control children (35.1 +/- 6.0). Administration of 2 mg/m2 body surface dexamethasone, iv, to normal children induced, 3 h later, a mean GH peak of 14.1 +/- 1.2 micrograms/L. This was significantly higher that the corticoid-induced GH peak in GH-deficient children (6.7 +/- 1.1 micrograms/L). The corticoid-induced areas under the secretory curve were 1130 +/- 55 and 616 +/- 54 for the control and GH-deficient children, respectively. GH release in children after dexamethasone administration followed the pattern previously described for adults, i.e. there were no modifications of basal GH levels in the first 2 h, the GH peak appeared around the third hour, and the GH levels remained increased until the fourth hour after dexamethasone administration. Individually considered, practically all control children, but only 2 of 12 GH-deficient children, presented a dexamethasone-induced GH peak over the 10 micrograms/L level. In both normal and GH-deficient patients, corticoids appeared just as potent a stimulus as propranolol-exercise and clonidine, and more potent than hypoglycemia. This new stimulus showed a pattern similar to that of the hypothalamic stimuli, but clearly different with respect to the pituitary one (GHRH), suggesting that corticoids activate GH secretion by acting at hypothalamic level. In conclusion, acute administration of corticoids could be a suitable test in the diagnostic armamentaria of GH-deficient states.     

Dose-response studies with biosynthetic human growth hormone (GH) in GH-deficient patients

Increasing doses of biosynthetic human GH (R-hGH) were given sc to seven GH-deficient patients for three consecutive 14-day periods (2, 4, and 6 IU/day at 2000 h), followed by 14 days of no GH therapy. At the end of each period each patient was hospitalized for frequent blood sampling from 2000 to 1100 h the following day. A dose-dependent increase in serum GH and serum insulin-like growth factor I (IGF-I) levels occurred. However, the time course of the serum IGF-I concentrations was different on the four occasions; there was a significant fall in the evening when no therapy was given (P less than 0.01), a significant increase after injections of 2 IU R-hGH, and constant levels during treatment with 4 and 6 IU R-hGH. Plasma glucose levels were within the normal range, with a significantly lower fasting level (at 0400 h) when no GH was given. Breakfast induced a plasma glucose rise when GH was administered, but no rise without GH, and a postprandial serum insulin response that was GH dose dependent. GH therapy increased serum FFA (P less than 0.05) and blood 3-hydroxybutyrate levels, but had no effect on blood alanine or lactate or serum triglyceride and cholesterol levels. We conclude that the serum IGF-I response to GH is dose dependent, and that a GH replacement dose of 2 IU/day (equalling 1.5 IU/m2.day) is insufficient to maintain normal diurnal serum IGF-I levels. Furthermore, a GH-independent diurnal variation in serum IGF-I in these patients is suggested. This GH preparation also has diabetogenic and lipolytic actions.     

Different modes of growth hormone (GH) administration do not change GH binding protein activity in man

OBJECTIVE Studies in rodents have shown GH binding protein (GHBP) levels to be dependent on the mode of GH administration. The aim is to determine whether GHBP levels in man are also modulated by the pattern of GH administration. PATIENTS Six GH deficient subjects participated in a randomized study in which 2 IU GH were administered either as (i) a continuous 24-hour infusion, (ii) two intravenous boluses or (iii) eight intravenous boluses every 3 hours. In a second study, six normal men received a single subcutaneous injection of 0 2 U/kg GH and GHBP activity was measured over 24 hours. Control data were obtained from an untreated group of six age-matched normal men. MEASUREMENTS GHBP activity was measured by immunoprecipitation using a monoclonal antibody that recognizes the human GHBP, and expressed as percentage specific binding of ¹²⁵I-GH in 50 μl of serum. RESULTS GHBP activity was not significantly different between the GH deficient and normal subjects. GHBP activity did not rise significantly during GH administration with each of the three intravenous patterns of delivery nor were there any significant differences between treatments. in the second study, GHBP activity did not change significantly following subcutaneous GH injection nor did results differ from untreated normal controls. CONCLUSIONS The level of GHBP in man is not dependent on GH secretory status or altered by short-term GH treatment or the mode of administration. These findings stand in contrast to GH treatment effects in rodents and suggest that GH regulation of GHBP may be different between species.     

Long-term effects of insulin-like growth factor (IGF)-I treatment on serum IGFs and IGF binding proteins in adolescent patients with growth hormone receptor deficiency

OBJECTIVE The aim of this investigation was to study the effect of relatively high dose IGF-I therapy given for several months, on serum levels of IGF-I, IGF-II and IGFBP-3, and on IGF-I pharmacokinetics In patients with growth hormone insensitivity due to GH receptor dysfunction. DESIGN AND PATIENTS Two adolescent subjects from Ecuador were treated with recombinant IGF-I at a dosage of 120μg/kg s.c. twice dally, in combination with a GnRH analogue for 8 months. MEASUREMENTS Serum was sampled at baseline and at 3–8 months, for determination of IGF-I, IGF-II and IGFBP-3 by radioimmunoassay, and for evaluation of IGFBPs and IGFBP-3 protease activity by Western ligand blot and protease assay, respectively. RESULTS Peak serum IGF-I levels ranged from 272 to 492μg/l. Mean serum IGF-II levels were decreased concurrently with the increase in IGF-I. Serum IGFBP-3 levels failed to rise with prolonged IGF-I treatment. There was no apparent change In the half-life of IGF-I during the treatment period. CONCLUSIONS IGF-I administration does not increase serum levels of IGFBP-3 or significantly alter IGF-I pharmacokinetics.     

Is further evaluation for growth hormone (GH) deficiency necessary in fibromyalgia patients with low serum insulin-like growth factor (IGF)-I levels?

OBJECTIVE: Fibromyalgia (FM) is characterized by diffuse pain, fatigue, and sleep disturbances; symptoms that resemble the adult growth hormone (GH) deficiency syndrome. Many FM patients have low serum GH levels, with a hypothesized aetiology of dysregulated GH/insulin-like growth factor (IGF)-I axis. The aim of this study was to assess the GH reserve in FM patients with low serum IGF-I levels using the GH-releasing hormone (GHRH)-arginine test. DESIGN: We retrospectively reviewed the GHRH-arginine data of 77 FM patients with low serum IGF-I levels referred to our tertiary unit over a 4-year period. RESULTS: Of the 77 FM patients, 13 patients (17%) failed the GHRH-arginine test. Further evaluation with pituitary imaging revealed normal pituitary glands (n=7), coincident microadenomas (n=4), empty sella (n=1) and pituitary cyst (n=1), and relevant medical histories such as previous head injury (n=4), Sheehan's syndrome (n=1), and whiplash injury (n=1). In contrast, the remaining 64 patients (83%) that responded to the GHRH-arginine test demonstrated higher peak GH levels compared to age and BMI-matched controls (n=24). CONCLUSION: Our data shows that a subpopulation of FM patients with low serum IGF-I levels will fail the GHRH-arginine test. We, thus, recommend that the GH reserve of these patients should be evaluated further, as GH replacement may potentially improve the symptomatology of those with true GH deficiency. Additionally, the increased GH response rates to GHRH-arginine stimulation in the majority of FM patients with low serum IGF-I levels further supports the hypothesis of a dysregulated GH/IGF-I axis in the pathophysiology of FM.     

Effects of growth hormone (GH) on plasma bone Gla protein in GH-deficient adults

Both deficiency and excess of GH are related to disturbances in calcium metabolism. Bone Gla protein (BGP) is the only specific marker of bone turnover identified in peripheral blood. We, therefore, determined plasma BGP in 21 adult GH-deficient patients treated with biosynthetic human GH in a double blind cross-over study. We also examined 9 patients with acromegaly before and after surgery. The GH-deficient patients had normal initial plasma BGP concentrations, whereas the acromegalic patients had highly significantly increased concentrations (P less than 0.001). During treatment with human GH, plasma BGP (and other nonspecific biochemical markers of bone turnover) increased significantly (P less than 0.001). During placebo treatment plasma BGP showed baseline values. In the acromegalic patients a significant decrease in plasma BGP concentrations was seen 1 week after surgery. The present study suggests that plasma BGP is a useful biochemical marker of the effect of treatment of both GH deficiency and GH excess/disorders.     

Continuation of growth hormone (GH) substitution during fasting in GH-deficient patients decreases urea excretion and conserves protein synthesis.

The consequences of GH deficiency during conditions in which endogenous GH release is acutely stimulated are largely unknown. Short-term fasting constitutes a robust GH stimulus, but the metabolic significance of GH during fasting is uncertain. To address both of these issues, we therefore evaluated the effect of GH on substrate metabolism during fasting in adults with GH deficiency. Seven hypopituitary GH-deficient patients were each studied twice during a 40-h fast: once with GH replacement continued and once with GH discontinued during the fast. After 40 h of fasting, protein synthesis and turnover were higher with than without GH replacement [phenylalanine incorporation (micromol/kg fat free mass/h): 36.6 +/- 1.2 (GH) vs. 32.8 +/- 1.4, P < 0.05; phenylalanine flux (micromol/kg fat free mass/h): 41.3 +/- 1.0 (GH) vs. 38.0 +/- 1.8, P < 0.05]. During continued GH replacement, urea excretion decreased during nighttime [urea excretion (mmol/24 h): 269 +/- 51 (GH) vs. 390 +/- 69, P < 0.05], and a significant decline in urea-N synthesis rate was found [urea-N synthesis rate (mmol/h): 14.7 +/- 1.6 (GH) vs. 21.1 +/- 2.2, P < 0.01]. GH replacement was associated with increased lipid oxidation [lipid oxidation (mg/kg per min): 0.91 +/- 0.07 (GH) vs. 0.70 +/- 0.03, P < 0.05]. Finally, continuation of GH induced moderate elevations in plasma glucose levels without significant changes in total glucose turnover or oxidation. In summary, continued GH substitution during fasting conserves nitrogen, which involves stimulation or maintenance of protein synthesis. Our data support the importance of GH replacement in hypopituitary adults.     

Growth hormone (GH)-binding protein in normal and GH-deficient dwarf rats.

There are GH-binding proteins (GHBPs) present in the blood of many species, and these correspond to the extracellular GH-binding domain of the GH receptor. In the rat, GHBP arises by alternative splicing of the GH receptor mRNA, but little is known of the physiological role of circulating GHBP, or its relationship with episodic GH secretion. We have developed a sensitive radioimmunoassay based on recombinant GHBP, and have measured rat GHBP levels in small samples of plasma from normal and GH-deficient dwarf rats. In normal adult rats, GHBP levels were two- to threefold higher in females than in males (16.6 +/- 0.8 vs 6.4 +/- 0.4 micrograms/l, P < 0.001), but this sex difference was not seen in dwarf rats. A continuous infusion of human GH in dwarf males raised plasma GHBP to 23.5 +/- 3.5 micrograms/l compared with 6.7 +/- 0.5 micrograms/l in sham-infused animals, whereas suppression of GH by continuous infusion of a long-acting somatostatin analogue in female dwarf rats had no effect on GHBP. In anaesthetized rats, large changes in plasma GH caused by i.v. administration of rat GH, somatostatin or GH-releasing factor did not affect GHBP acutely. Both GH and GHBP were also measured in serial blood samples from conscious normal and dwarf rats. A sexually dimorphic GH secretory pattern was observed in both strains. Males showed peaks and troughs of GH every 3 h varying over a 100-fold range, whereas females exhibited more continuous GH secretion. Despite the large fluctuations in endogenous GH, GHBP levels remained relatively constant in individual normal or dwarf males, as well as in females of both strains, and there was no significant correlation between GH and GHBP either in individual rats or as a group. Our results suggest that GHBP is GH-dependent in the longer term, and that the higher GHBP levels in female rats require their continuous GH secretory pattern. However, plasma GHBP levels remain stable and are not affected by acute changes in endogenous or exogenous GH.     

Effects of growth hormone treatment on serum levels of insulin-like growth factors (IGFs) and IGF binding proteins 1-4 in postmenopausal women

BACKGROUND AND OBJECTIVE: Insulin-like growth factor binding proteins (IGFBPs) modulate the actions and bioavailability of insulin-like growth factors (IGFs), however, their regulation in vivo is incompletely understood. In this study we investigated the effects of different doses of growth hormone (GH) on circulating levels of IGFs and IGFBPs. DESIGN: The study was double-blind and placebo-controlled. Patients were treated with either GH in doses of 0.05, 0.10, or 0.20 lU/kg/day of placebo for one week. PATIENTS: Forty post-menopausal women aged 52-73 years with low bone mass. MEASUREMENTS: Serum IGF-I and IGF-II were measured by RIA while IGFBP-1-3 were measured by Western ligand blot (WLB) and compared with determinations by specific immunoassays. IGFBP-4 was measured by WLB alone. RESULTS: Both IGF-I (P < 0.001) and IGF-II (P < 0.01) increased significantly during GH treatment. Additionally, IGFBP-1 (P < 0.001) and IGFBP-2 (P < 0.001) decreased significantly while IGFBP-3 (P < 0.001) and IGFBP-4 (P < 0.05) increased all in a dose-dependent manner. Stepwise (backwards) multiple regression analyses showed that the changes in IGF-I and IGF-II, and age correlated with the change in serum IGFBP-1. Both GH-dosage, the increase in IGF-II, and body mass index correlated with the decrease in IGFBP-2. Furthermore, the increase in serum IGF-I, IGF-II, and triiodothyronine correlated with the increase in IGFBP-3. Moreover, GH-dosage correlated with the increase in serum IGFBP-4. CONCLUSION: GH significantly increased serum IGF-I, IGF-II, IGFBP-3, and IGFBP-4 and decreased serum IGFBP-1 and IGFBP-2 in post-menopausal women.     

Stimulation of the 150-kilodalton insulin-like growth factor-binding protein-3 ternary complex by continuous and pulsatile patterns of growth hormone (GH) administration in GH-deficient patients

In the circulation insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3), and the acid-labile subunit (ALS) form a 150-kDa ternary complex that is of importance for the regulation of IGF-I bioactivity. GH administration is known to increase each of the single components of the ternary complex, and in GH-deficient rats formation of the 150-kDa complex is induced more by continuous than by pulsatile GH patterns. The aim of the present studies was to study the effects of the GH administration pattern on the formation of the 150-kDa ternary complex in humans. A fixed total GH dose (2 IU/m2-24 h) was administered iv randomly as 1) continuous infusion or 2) eight bolus injections to five GH-deficient patients over a period of 24 h. GH administration significantly increased serum IGF-I and IGFBP-3 levels and the IGF-I/IGFBP-3 ratio. IGF-I levels increased most pronouncedly after continuous administration (P < 0.01). Serum ALS levels increased significantly (both P < 0.005) from 94+/-21 to 180+/-29 (infusion) and from 85+/-17 to 155+/-17 nmol/L (pulses). Employment of neutral size exclusion chromatography enabled separation of IGFBP-3 in ternary complex and noncomplex-bound fractions. IGFBP-3 in the ternary complex increased significantly after GH administration [by 44% (P = 0.048) during infusion and by 62% (P = 0.004) during bolus]. The noncomplex-associated IGFBP-3 fraction, however, did not increase significantly after GH administration (P = NS). Finally, formation of the ternary complex was unaffected by the pattern of GH delivery. In conclusion, short-term GH administration increased all components of the 150-kDa ternary complex. Higher levels of IGF-I after constant GH exposure could indicate an increased bound fraction. However, the GH pattern did not influence the induction of the ternary complex itself. Continuous and intermittent GH patterns may be clinically equally effective during long-term GH therapy, as judged by levels of the components of the ternary complex.     

Effects of a 7-day continuous infusion of octreotide on circulating levels of growth factors and binding proteins in growth hormone (GH)-treated GH-deficient patients

In patients with acromegaly, clinical improvement has been reported after octreotide (OCT) treatment, even in cases of only a moderate suppression of growth hormone (GH) levels. In rats, OCT suppresses IGF-I mRNA expression and generation of serum and tissue IGF-I levels. A direct effect of OCT on the IGF system could have therapeutical implications in diabetes mellitus, cardiovascular disease, and certain malignancies in which IGF-I might be involved. The aim of this study was to examine possible GH-independent effects of OCT on IGF components in humans. Six GH-deficient (GHD) patients were studied for 24 h after each of the following treatment regimens (each of 1 weeks duration): (a) daily s.c. GH injection (2 IU/m(2)); (b) as (a) + continuous s.c. infusion of OCT (200 microg/24 h) by means of a portable pump (Nordic Infuser); (c) no treatment. Serum GH binding protein (GHBP) levels tended to be lower after GH and OCT than after GH alone (P =0.10). OCT reduced the GH induced increase in serum IGF-I levels (P<0.05, ANOVA). Mean integrated levels (microg/l) were 359.1+/-49.6 (GH), and 301.6+/-58.9 (GH+OCT). OCT did not significantly reduce serum IGFBP-3 levels (microg/l) [3460+/-270 (GH), and 3112+/-435 (GH+/-OCT);P =0.14]. Serum levels of free IGF-I (P =0.39), IGF-II (P =0.54), and of the acid-labile subunit (ALS) of the ternary complex (P =0.50) were similar during GH+/-OCT as compared with GH alone. After 1 week off GH treatment, significantly lower levels of IGF-I, IGF-II, IGFBP-3, and ALS were recorded (P<0.001). Serum IGFBP-1 levels were significantly higher after GH+OCT than after GH alone (P<0.0001), and levels were even higher without GH. Serum insulin levels (pmol/l) were significantly higher after GH alone as compared with no GH (P<0.05, ANOVA), whereas OCT partly suppressed the insulinotropic effect of GH (P<0. 05) [mean: 114.5+/-33.0 (GH), 91.3+/-29.6 (GH+OCT), 65.9+/-22.5 (no GH)]. This was also reflected in higher blood glucose levels during GH+OCT. Finally, GH+OCT reduced glucagon levels significantly as compared with GH alone (P =0.02). In conclusion, 7 days' administration of OCT to GH-treated GHD patients slightly attenuated serum IGF-I generation, and tended to decrease levels of the other components of the 150 kDa ternary complex. Whether these effects are mediated directly by OCT or indirectly via the accompanying changes in insulin levels remains to be investigated.