Hepatic Growth Hormone Receptor Research Articles

Study of the hepatic growth hormone (GH) receptor at different ages in chickens selected for a good feed conversion (FC) and a fast weight gain (GL)

The influence of genetic selection for improved feed conversion (FC) and fast growth (GL) in broiler chickens, on the hepatic growth hormone receptor was investigated as a function of age. Selection for improved feed conversion resulted in lean chickens, whereas selection for fast growth resulted in fat chickens. Growth hormone receptor characteristics were determined in liver microsomal fractions and plasma GH concentrations were measured by radioimmunoassay. Embryos from the FC line showed higher specific GH binding than GL embryos at day 16 of embryonic development only (P<0.05). On day 18 of embryonic development, the FC line had slightly more GH receptors than the GL line (P<0.05), whereas simultaneous plasma GH concentrations were greater in the GL line. The effect of selection on hepatic growth hormone binding was greatest in 4 week old growing chicks at which age the GL line showed a 2- to 3-fold higher % of specific binding than the FC line (P<0.001). The difference at this stage is probably due to down regulation of the receptor by the significantly higher GH concentrations in the FC line. The adult GL chickens also showed higher specific binding than FC, but the difference was less pronounced than in the growing stage (P<0.05). This was due to a higher number of GH receptors, while receptor affinity was unchanged. Because no line difference in plasma GH concentrations was found in adult hens, other unknown mechanisms probably play a role in determining differences in GH receptor binding between these selected lines at older ages.

Experimental diabetes mellitus in a teleost fish. II. Roles of insulin, growth hormone (GH), insulin-like growth factor-I, and hepatic GH receptors in diabetic growth inhibition in the goby, Gillichthys mirabilis

Insulin-dependent diabetes mellitus (IDDM), when untreated or poorly controlled in mammals, results in growth retardation. To determine whether the same relationship exists in an ectothermic vertebrate, IDDM-like symptoms were induced in a teleost fish, the goby Gillichthys mirabilis, by surgical removal of its pancreatic endocrine (islet) organ. Isletectomized (Ix) gobies lost body weight, their skeletal growth was retarded, as measured by changes in body length, and they exhibited a 50% reduction in cartilage 35SO4 incorporation in vitro, consistent with changes that occur in mammals with IDDM. Injections of bovine insulin into the Ix fish restored body growth parameters to control levels and stimulated cartilage 35SO4 incorporation in a dose-related manner. In contrast to mammals with IDDM, which are resistant to GH action, injection of teleost GH stimulated cartilage 35SO4 incorporation in the Ix fish. Furthermore, whereas cartilage from rats with IDDM is resistant to stimulation by insulin-like growth factor-I (IGF-I) in vitro, cartilage explants from the Ix fish were highly responsive to recombinant bovine IGF-I, exhibiting a dose-dependent stimulation of 35SO4 incorporation. As far as we are aware, these results represent the first demonstration of diabetic growth inhibition in an ectothermic vertebrate. This inhibition is similar to that which occurs in mammals with IDDM in some respects, but is different in others, as the diabetic fish did not develop resistance to growth stimulation by either GH or IGF-I. While these results support a role for insulin in maintaining the GH-IGF-I-growth axis in this ectothermic vertebrate, there may be important differences in the role of insulin in the promotion of anabolic processes.

Experimental diabetes mellitus in a teleost fish. II. Roles of insulin, growth hormone (GH), insulin-like growth factor-I, and hepatic GH receptors in diabetic growth inhibition in the goby, Gillichthys mirabilis.

Insulin-dependent diabetes mellitus (IDDM), when untreated or poorly controlled in mammals, results in growth retardation. To determine whether the same relationship exists in an ectothermic vertebrate, IDDM-like symptoms were induced in a teleost fish, the goby Gillichthys mirabilis, by surgical removal of its pancreatic endocrine (islet) organ. Isletectomized (Ix) gobies lost body weight, their skeletal growth was retarded, as measured by changes in body length, and they exhibited a 50% reduction in cartilage 35SO4 incorporation in vitro, consistent with changes that occur in mammals with IDDM. Injections of bovine insulin into the Ix fish restored body growth parameters to control levels and stimulated cartilage 35SO4 incorporation in a dose-related manner. In contrast to mammals with IDDM, which are resistant to GH action, injection of teleost GH stimulated cartilage 35SO4 incorporation in the Ix fish. Furthermore, whereas cartilage from rats with IDDM is resistant to stimulation by insulin-like growth factor-I (IGF-I) in vitro, cartilage explants from the Ix fish were highly responsive to recombinant bovine IGF-I, exhibiting a dose-dependent stimulation of 35SO4 incorporation. As far as we are aware, these results represent the first demonstration of diabetic growth inhibition in an ectothermic vertebrate. This inhibition is similar to that which occurs in mammals with IDDM in some respects, but is different in others, as the diabetic fish did not develop resistance to growth stimulation by either GH or IGF-I. While these results support a role for insulin in maintaining the GH-IGF-I-growth axis in this ectothermic vertebrate, there may be important differences in the role of insulin in the promotion of anabolic processes.

Ontogeny of the porcine insulin-like growth factor system

The developmental expression of the individual components of the insulin-like growth factor (IGF) system in pigs was examined. Serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels were low during fetal life and increased during postnatal development. Levels of mRNAs encoding these proteins were not greater for liver than for nonhepatic tissues (skeletal muscle, lung, kidney) and did not increase during the postnatal period, whereas hepatic growth hormone (GH) receptor mRNA expression was increased postnatally. Serum IGF-II levels exceeded IGF-I levels at all developmental stages examined and both exhibited postnatal increases. IGF-II mRNA abundance, in contrast, was high in the fetal tissues with the exception of lung and declined during the perinatal transition. Hepatic IGFBP-2 mRNA and serum IGFBP-2 levels increased during the latter half of gestation and then declined postnatally. The levels in muscle and liver of type I IGF receptors and the corresponding mRNAs also exhibited postnatal decreases. The discordance of changes in hepatic IGF-I and IGF-II mRNA abundance with serum IGF levels during the postnatal period does not support the concept that liver is the primary endocrine source of IGFs in the young pig. The postnatal increases in serum IGF levels may reflect decreased plasma clearance rates of these peptides which may be related to the transition in IGFBP type from IGFBP-2 to IGFBP-3 in blood and the reduced tissue expression of IGF receptors.

NUTRITION IS AN IMPORTANT REGULATOR OF THE GROWTH HORMONE BINDING PROTEIN

Top of pageAbstract Food intake is known to have a major role in the regulation of hepatic GH receptors in rats. To evaluate effects of nutrition on the GH binding protein (GHBP), a soluble short form of the GH receptor, we have studied children presenting with celiac disease and children with obesity. Eight girls and two boys, aged 3-14 yr, all prebubertal, with short stature (- 4.2 ± 0.2 SD from normal height) had celiac disease. Their plasma IGF1 level was very low (mean ± SEM = 66.3 ± 10.3 ng/ml vs normal value for age = 216 ± 22 ng/ml). GHBP (16.4 ± 2.2% of radioactivity) was significantly lower than the value of prepubertal normal children (24.8 ± 1.7% of radioactivity). In six boys and two girls with obesity (+ 4.2 ± 0.4 SD from normal weight), aged 4-10 yr prepubertal, with normal height, GHBP was very high (56.3 ± 3.5% of radioactivity). The increased GHBP level was related to high binding capacity without change in affinity. The growth defect presented by children with celiac disease is associated with partial GH resistance and low GH receptor level. On the contrary, children with obesity and normal growth, have a high GH receptor level.

REDUCED EXPRESSION OF THE HEPATIC GROWTH HORMONE (GH) RECEPTOR IN EXPERIMENTAL UREMIA

In uremia reduced longitudinal growth and decreased hepatic IGF-I secretion despite elevated GH serum levels point to a resistance to the action of GH, which could be a consequence of a reduced hepatic GH receptor (R) expression. To addressthis hypothesis we studied the hepatic GH-R mRNA content in uremic female SD rats (n=7 per group) subjected to 5/6 nephrectomy (U) compared to sham operated pairfed (PC) or ad libitum fed (aLC) controls. Animals were treated with 10 IU rhGH/kg/day, or solvent for 10 days. Total RNA was prepared from rapidly frozen liver tissue and the GH-R mRNA quantified by solution hybridization. Mean (±SD) weight gain was lower in U (21.4±7.9 g) compared to PC (24.1±5.9; P<0.005) and aLC (33.5±6.3; P<0.005). Hepatic GH-R mRNA was reduced in U (0.79±0.39 amol/ug DNA) vs PC (1.46±0.32; P<0.005) and vs aLC (2.66±0.73, P<0.001). Exogenous rhGH slightly increased (n.s.) GH-R mRNA in all groups. Plasma GH binding protein (BP) levels (RIA) in U were 11.1±4.4 ng/ml, in PC 8.2±2.3, in aLC 5.7±2.5 (P<0.01). We conclude that experimental uremia is accompanied by a marked reduction of hepatic GH-R expression. The data in the pairfed animals indicate that this effect is only partially attributable to malnutrition. Increased plasma GHBP levels in U might be interpreted as a consequence of reduced renal clearance.

Growth hormone receptor gene expression in sex-linked dwarf Leghorn chickens: evidence against a gene deletion

GH receptor (GHR) mRNA has been identified in peripheral (liver and muscle) and central (brain and hypothalamus) tissues of sex-linked dwarf (SLD) Leghorn chickens. Total RNA was extracted from the tissues of immature (1 week, 4 week), pubertal (16 week) and adult (> 24 weeks) SLD and K (the normally growing strain) Leghorn chickens. In both groups and all tissues, an mRNA moiety of 4.4 kb hybridized with cRNA probes derived from the rabbit hepatic GHR sequence. An additional low-abundance transcript of 2.8 kb was also identified in some tissues. An age-related increase in expression was observed in K and SLD hepatic GHR mRNA, suggesting normal regulation of SLD GHR gene transcription. Amplification of cDNA from K and SLD tissues in the presence of oligonucleotide primers coding for the intracellular or extracellular domains of the chicken GHR generated electrophoretically separable fragments of expected size. Restriction enzyme digestion of the products with EcoRI, BstNI, HaeIII, NcoI or BamHI produced smaller moieties of expected sizes in both strains. These results demonstrate that, in contrast to broiler SLDs, a GHR gene deletion is not responsible for the GHR dysfunction in Leghorn SLDs. Although the actual defect in GHR gene expression in SLD Leghorns remains to be identified, this study demonstrates that sex-linked dwarfism, like Laron dwarfism, is due to a heterogeneity of lesions.

Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with type 1 (insulin-dependent) diabetes mellitus.

Serum levels of insulin-like growth factor I are reduced in patients with Type 1 (insulin-dependent) diabetes mellitus. To evaluate the role of the hepatic growth hormone receptor in the decreased serum concentrations of insulin-like growth factor I, serum levels of the high affinity growth hormone-binding protein, which is qualitatively and quantitatively related to the hepatic growth hormone receptor, and of insulin-like growth factor I were measured in 70 children and adolescents with Type 1 diabetes and 105 healthy control children. Analysis of variance revealed a significant negative effect of Type 1 diabetes on serum levels of the growth hormone-binding protein and of insulin-like growth factor I. In the diabetic patients, serum levels of the growth hormone-binding protein were positively related to body mass index and to insulin dose per kg body weight, and were not influenced by pubertal stage, gender, or plasma levels of haemoglobin A1c. Serum levels of insulin-like growth factor I increased during early puberty reaching peak levels at mid-puberty and decreasing thereafter. No relationship was found between serum levels of growth hormone-binding protein and of insulin-like growth factor I. Our data suggest that decreased liver somatogenic receptor levels, as reflected by the concentrations of circulating growth hormone-binding protein, play a minor role in the suppressed concentrations of circulating insulin-like growth factor I. Post-growth hormone receptor defects or changes in the insulin-like growth factor binding proteins probably contribute more to the lower serum levels of insulin-like growth factor I.

Endogenous growth hormone controls high plasma levels of 3,3′,5-triiodothyronine (T 3) in growing chickens by decreasing the T 3-degrading type III deiodinase activity

The influence of endogenous GH levels on peripheral monodeiodination activity has been investigated in growing chickens at the age of 4 weeks, when they normally show no T 3 increase after GH injection. Injection of anti-GH serum decreased plasma T 3 and increased plasma T 4. Three d and 1 week after hypophysectomy, plasma T 3 was also markedly decreased, while T 4 was only slightly affected, hepatic 5′D-I activity showed a transient decrease, but 5D-III activity was highly increased, as were the number of hepatic GH receptor sites. Injection of GH in hypophysectomized chickens decreased 5D-III activity and increased plasma T 3. GH receptor-deficient dwarf chickens had decreased plasma T 3 and increased plasma T 4 and hepatic 5′D-I and 5D-III activities compared to their normally-growing siblings. GH administration could only affect T 3 and 5D-III in the non-dwarf siblings, which showed higher basal 5D-III activity compared to the non-responsive age-matched chickens of the Hisex strain used in the other experiments. It can be concluded that endogenous GH is an important factor in the control of plasma T 3 levels in growing chickens due to its influence on the activity of the T 3-degrading type III deiodinase. The effectiveness of exogenous GH administration to acutely increase plasma T 3 probably depends on the balance between the injected dose and the endogenous GH concentration, the hepatic GH receptor availability and the hepatic type III deiodinase level.

Effects of intermittent growth hormone or insulin-like growth factor 1 administration in the neonatal dwarf rat.

To further evaluate the role of growth hormone (GH) in the neonatal period, the effects of GH or insulin-like growth factor 1 (IGF-1) administration were studied in the neonatal GH-deficient rat. Groups of pups from newborn litters were randomized to receive twice daily subcutaneous injections of recombinant bovine growth hormone (bGH, 5 micrograms), recombinant human IGF-1 (10 micrograms) or saline from the second to twelfth day of life. The effects on growth parameters, serum IGF-1 concentration, body composition and hepatic GH receptor binding were assessed. bGH-treated animals showed increases in body weight gain (p = 0.01), serum IGF-1 (p < 0.01), carcass nitrogen (p < 0.001) and carcass water (p < 0.001) compared to IGF-1 or saline-treated animals. No differences in these parameters were noted between IGF-1 and saline-treated groups. bGH-treated animals showed a significantly lower hepatic GH receptor binding (p < 0.01) compared to the other two groups. The demonstration of anabolic responses to GH administration in the neonatal period has implications for the possible role of GH in fetal and neonatal growth.

Regulation of the hepatic growth hormone receptor and serum growth hormone-binding protein during pregnancy in the mouse: effects of litter size

The regulation of hepatic GH receptor (GHR) and serum GH-binding protein (GHBP) during pregnancy in the mouse was investigated by manipulating the number of conceptuses carried by the dam. Animals carrying 1-4 conceptuses had significantly lower amounts of hepatic GHR (GH-binding activity) than mice carrying 10-13 conceptuses on days 9 and 13 of pregnancy. There was no significant difference in hepatic GHR on day 17 of pregnancy between animals carrying 1-4 and 10-13 conceptuses. Animals carrying 1-4 conceptuses had significantly lower concentrations of GHBP in serum than animals carrying 10-13 conceptuses on days 9, 13, and 17 of pregnancy. The relative amounts of liver GHR- and GHBP-encoding messages in animals with low and high conceptus numbers were investigated by Northern analysis. There were higher levels of both messages in animals carrying 10-13 conceptuses than in mice carrying 1-4 conceptuses. On day 13 of pregnancy, animals carrying 10-13 conceptuses had significantly higher levels of GHBP-encoding message than animals carrying 1-4 conceptuses. Total hepatic mass was not significantly different between animals with low and high conceptus numbers. No significant difference was found in GHBP concentration between blood from the uterine vein and the trunk in 17-day pregnant animals. Mouse placental lactogen-I (mPL-I), mPL-II, GH, and corticosterone concentrations were measured by RIA and related to hepatic GHR activity and serum GHBP concentration. Hepatic GHR activity and serum GHBP concentration were significantly correlated with each other on days 9, 13, and 17 of pregnancy. Hepatic GHR activity was significantly correlated with mPL-I and mPL-II on day 9 of pregnancy. GHBP concentration was significantly correlated with mPL-I and mPL-II on day 9 of pregnancy and with mPL-II and GH on day 13 of pregnancy. Data are consistent with the hypothesis that mPL-I, mPL-II, and GH may affect hepatic expression of the GHR/GHBP gene during pregnancy in the mouse.

Regulation of hepatic growth hormone receptors in coho salmon ( Oncorhynchus kisutch)

Factors potentially regulating hepatic growth hormone (GH) receptors in coho salmon ( Oncorhynchus kisutch) have been investigated. From December to June of the first year, relative changes in hepatic 125I-sGH binding and 35SO 4 incorporation by ceratobranchial cartilage were similar. Stunted salmon, which in seawater have elevated plasma GH yet fail to grow, showed lower hepatic 125I-sGH binding than did normally growing seawater salmon. However, MgCl 2 treatment of stunts' membranes to reveal total specific binding of 125I-sGH indicated receptor occupation by endogenous sGH. Total specific 125I-sGH binding was low in seawater stunts and remained low if these fish remained unfed after return to fresh water, but increased approximately twofold upon feeding. Total specific binding in fasted salmon in fresh water showed a trend toward decreased levels by 1 week; by 3 weeks, binding was 40% lower than in fed fish. There was a positive correlation ( r = 0.600) between condition factor and total specific binding in fed and fasted salmon in fresh water. Two weeks after hypophysectomy total speck binding was 50% lower than in sham-operated control salmon, indicating pituitary regulation of GH receptors. GH treatment reduced both free and total 125I-sGH binding in salmon examined 24 hr after treatment. Treatment with recombinant bovine insulin-like growth factor I, thyroxine, or cortisol did not affect free 125I-sGH binding. Both the pituitary and nutrition appear to be prime regulators of hepatic GH receptors in coho salmon.

Developmental expression of hepatic growth hormone receptor and insulin-like growth factor-I mRNA in the chicken

We have examined the ontogeny of expression of growth hormone (GH) receptor (GHR) and insulin-like growth factor-I (IGF-I) mRNA in chicken liver from day 13 of incubation until 31 weeks of age. The profiles of GHR and IGF-I mRNA levels were compared to developmental changes in body weight and plasma levels of GH and IGF-I. In the embryo, hepatic GHR mRNA was not detectable until day 15, highest on days 17 and 19, and then declined at hatching (day 21). Following an initial 2-week delay after hatching, there was a progressive increase in hepatic GHR mRNA which continued after the birds reached mature body weight. Plasma GH reached peak levels at 3–4 weeks of age and then fell sharply until maintenance of a low basal level after 10 weeks of age. Thus, there appears to be a strong inverse relationship between expression of the GHR and basal plasma GH levels in the prepubertal chicken. Although IGF-I mRNA was undetectable in embryonic liver by Northern blot analysis, there is a good correlation between expression of hepatic IGF-I mRNA and the plasma IGF-I profile during post-hatching development in the chicken. The highest levels of IGF-I mRNA were reached at 4 weeks of age which was followed by a slow decline to the basal levels maintained after 10 weeks of age. It appears that the decline in plasma IGF-I lags considerably behind the sharp fall in plasma GH levels and expression of hepatic IGF-I mRNA. These observations indicate that some of the regulatory elements of the GH → GHR → IGF-I pathway are not tightly coupled during late post-hatching development of the chicken.

Somatotropic and lactotropic receptors in transgenic mice expressing human or bovine growth hormone genes.

The somatotropic and lactotropic receptors were studied in liver microsomal preparations from transgenic mice carrying the human growth hormone (hGH) or bovine growth hormone (bGH) gene fused to mouse metallothionein-I (MT) or phosphoenolpyruvate carboxykinase promoter/regulator (PEPCK). Specificity studies indicated that, similarly to normal mice, liver microsomes from the transgenic animals possess a mixed population of somatotropic and lactotropic binding sites. In transgenic animals of both sexes, the binding capacity of somatotropic receptors was significantly increased without corresponding changes in affinity. Expression of the MT-hGH hybrid gene was associated with the induction of somatotropic receptors which was approximately twice as great as that measured in animals expressing the MT-bGH hybrid gene. The binding capacity of lactotropic receptors in liver microsomes (quantitated by the use of labelled ovine prolactin) was increased 2-3 fold in transgenic females and approximately 10-fold in transgenic males as compared to the respective normal controls. We conclude that lifelong excess of GH up-regulates hepatic GH and prolactin receptors, and that lactogenic activity of GH is not essential for induction of prolactin receptors in the liver of transgenic mice.

Expression of the growth hormone receptor and growth hormone-binding protein during pregnancy in the mouse.

A 20-fold increase in the relative expression of the hepatic GH-binding protein (GHBP)-encoding message between nonpregnant and 17-day pregnant mice was found. The hepatic GH receptor (GHR)-encoding message increased 8-fold between nonpregnant and pregnant mice. The increase in both messages began on day 9 of pregnancy. The steady state level of the GHBP-encoding message continued to increase steadily until day 17 of pregnancy; however, by day 13 of pregnancy, the steady state level of the GHR-encoding message reached a plateau that continued to day 17. The ratio between the GHBP- and GHR-encoding messages gradually increased during the second half of pregnancy, reaching a maximum on day 17. There was a 10- to 16-fold increase in GH-binding capacity in liver microsomes and a 30- to 50-fold increase in serum GH-binding capacity between nonpregnant and late pregnant mice. The increase in hepatic GH-binding capacity began on day 9 of pregnancy and reached a plateau on day 11, which was maintained until the end of gestation. The increase in serum GH-binding capacity began on day 9 of pregnancy and continued to increase until day 17. No significant change in mouse (m) GHR (mGHR) or mGHBP affinity constants were observed between nonpregnant and pregnant mice; however, the mGHR had a 20-fold greater affinity for mGH than did the mGHBP. The serum GH concentration increased in the second half of pregnancy. The GHBP-bound and the free fractions of GH during pregnancy were predicted. While the bound fraction of GH is predicted to parallel the total GH concentration measured by RIA, the concentration of free mouse GH remains unchanged during pregnancy.

Roles of pulsatility and continuity of growth hormone (GH) administration in the regulation of hepatic GH-receptors, and circulating GH-binding protein and insulin-like growth factor-I.

GH secretion in the male rat is characterized by regular GH peaks of high amplitude, and their GH receptors and GH-binding protein (BP) are low. Female rats have a more continuous secretion, and their GH receptors and GH-BP are high. To determine how the pattern of GH delivery may affects the physiological responses to the hormone, hypophysectomized male rats were infused with human GH (1.5 U/kg.day) for 5 days through an implanted iv cannula in either a pulsatile manner (for 5 min every 3 h) or continuously. We then measured free and total (after MgCl2 treatment) somatogenic and lactogenic receptors in hepatic cell membranes, and GH-BP and immunoreactive insulin-like growth factor-I (IGF-I) in serum. The concentrations of occupied, but not free, somatogenic and lactogenic binding sites were higher 5 min after a 5-min infusion of human GH than 90 min after the infusion. Consequently, the total levels (free plus ligand binding) of somatogenic and lactogenic receptors were also higher 5 min after a GH pulse than after 90 min. The levels of circulating GH-BP were higher 90 min than 5 min after a GH pulse, and the serum IGF-I levels did not differ between these time points. The concentrations of free and total somatogenic and free lactogenic receptors in the liver, as well as GH-BP and IGF-I in circulation were higher and body weight gain was lower in rats given continuous GH infusion than after pulsatile infusions. It is concluded that the nature of GH-levels profile has a marked influence on the interrelationship of GH, GH receptors, GH-BP, serum IGF-I and growth, whereby the later is stimulated maximally by pulsatile GH-levels, while the receptor and GH-BP are enhanced maximally by continuous levels. The basis for this discrepancy may lay in the competitive power of GH-BP toward GH receptor binding. A pulsatile GH pattern induced cyclicity in the levels of hepatic cell membrane GH receptors and circulating GH-BP. It is suggested that these factors are regulated in a similar way by the plasma GH pattern in pituitary intact rats.

5 Pseudohypopituitary syndromes

In a child with short stature, the finding of normal or elevated GH levels in the presence of low concentrations of IGF-I raises the following possibilities. (1) A modification of the GH molecule, which is still detected by RIA, but inactive biologically. Therefore, an RRA or bioassay for hGH should result in considerably lower GH measurements compared with RIA determinations in the same sample. As both bioassays as well as RRAs are not widely available and are hampered by several difficulties, few children with this presumptive diagnosis have been described. So far, it has not been possible to define a specific molecular defect in one of these patients. (2) Abnormalities of the GH receptor or postreceptor mechanisms lead to a GH insensitivity syndrome. Laron-type dwarfism is usually due to a deletion in the gene for hepatic GH receptors: the serum binding protein for GH is absent. In three additional populations, the Pygmies of Zaire, the little women of Loja in Ecuador and the Mountain Ok people in Papua New Guinea, alterations of GH receptor function have been described. Finally, some reports describe patients with normal or elevated serum levels of both growth hormone and IGF-I in whom resistance to IGF has been implied in the pathogenesis of small stature.

Roles of pulsatility and continuity of growth hormone (GH) administration in the regulation of hepatic GH-receptors, and circulating GH-binding protein and insulin-like growth factor-I

Roles of pulsatility and continuity of growth hormone (GH) administration in the regulation of hepatic GH-receptors, and circulating GH-binding protein and insulin-like growth factor-I

Ovine placental lactogen is a potent somatogen in the growth hormone (GH)-deficient rat: comparison of somatogenic activity with bovine GH.

The somatogenic effects of recombinant ovine placental lactogen (oPL) were investigated in the GH-deficient dwarf rat and compared to those of identical doses of recombinant bovine GH (bGH) in three independent studies. Both oPL and bGH treatments resulted in an increase (P less than 0.05) in body weight gain compared to that in saline controls, with oPL treatment being more potent than bGH (P less than 0.05). In promoting linear growth, oPL was more potent (P less than 0.05) than bGH in some instances. The nitrogen content of dry carcass matter was increased with oPL treatment compared to saline (P less than 0.05), with a nonsignificant increase in bGH-treated animals. Carcass fat was similarly reduced by both oPL and bGH treatment (P less than 0.05) compared to saline. Serum insulin-like growth factor-I (IGF-I) concentrations were increased significantly (P less than 0.05) by both oPL and bGH treatments, with a significantly greater effect of oPL suggested in one study. No increase in hepatic IGF-I mRNA was evident with either treatment, suggesting that the increase in serum IGF-I is due to posttranscriptional mechanisms. The expression of IGF-binding protein-3 hepatic mRNA was increased (P less than 0.05) with bGH treatment compared to that after saline treatment, but was unaffected by oPL treatment, indicating regulation by GH at the transcriptional level. The binding of [125I]bGH to hepatic membrane preparations demonstrated no difference in specific binding compared to that in saline controls. However, [125I]oPL specific binding was greater in oPL-treated animals (P less than 0.05). Animals treated with bGH had reduced (P less than 0.05) hepatic GH receptor mRNA compared to saline controls, but oPL treatment had no effect. Thus, oPL is a potent anabolic and lipolytic agent in the dwarf rat, exerting greater somatogenic effects on some parameters than bGH. Our data suggest differences in receptor binding and effects on GH receptor and IGF-binding protein-3 expression with these two treatments, raising the possibility of actions through different pathways or differential effects at the GH receptor level.

Decreased serum insulin-like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease.

To determine whether chronic hypoxemia results in alterations in endocrine function that may contribute to growth failure, we measured growth hormone (GH), somatomedins (insulin-like growth factors I and II, IGF-I and IGF-2), hepatic growth hormone receptors, and circulating IGF-binding proteins IGFBP-3 and IGFBP-2 in 12 newborn lambs with surgically created pulmonic stenosis and atrial septal defect, and in 10 controls. During chronic hypoxemia (oxygen saturation of 60-74% for 2 wk), weight gain was 60% of control (hypoxemic, 135 +/- 20 vs. control, 216 +/- 26 g/d, P less than 0.02). IGF-I was decreased by 43% (hypoxemic 253.6 +/- 29.3 SE vs. control 448.0 +/- 75.5 ng/ml, P = 0.01), whereas GH was unchanged (19.9 +/- 5.1 vs. 11.9 +/- 3.0 ng/ml, NS). The increase in IGF-1 was associated with a decrease in IGFBP-3 (hypoxemic, 5.09 +/- 1.25 vs. control, 11.2 +/- 1.08 arbitrary absorbency units per mm (Au.mm), P less than 0.01), and increase in IGFBP-2 (0.47 +/- 0.03 vs. 0.19 +/- 0.13 Au.mm, P less than 0.05), but no significant downregulation of hepatic GH receptors (hypoxemic, 106.1 +/- 20.1 vs. control, 147.3 +/- 25.9 fmol/mg, NS). Thus, chronic hypoxemia in the newborn is associated with a decrease in IGF-I and IGFBP-3 in the face of normal GH. This suggests peripheral GH unresponsiveness, similar to protein-calorie malnutrition or GH receptor deficiency dwarfism, but mediated at a level distal to the hepatic GH receptor.