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ABSTRACT
The individual effects of GH and thyroxine (T4) on protein metabolism were determined in dwarf and normal mice in vivo. The hormone deficiencies of dwarf mice (low serum concentrations of GH and T4) resulted in decreased protein synthesis rates in skeletal muscle and liver, but no difference in synthesis rates in heart. The efficiency of synthesis (g protein/g RNA per day; KRNA) was lower in all three tissues in dwarf compared with normal mice, but effects on RNA concentration were not consistent; there was no change in muscle, a decrease in liver and an increase in heart.
Treatment of dwarf mice for 9 days with either human GH or T4 caused increases in body weight and length. Protein synthesis rates were increased in muscle, liver and heart by either hormone, though much more so with T4 than GH. In muscle and liver both GH and T4 treatment resulted in an increased RNA concentration, but T4 treatment also increased KRNA. In heart, both GH and T4 increased KRNA with no change in RNA concentration. GH caused no significant changes in protein degradation rates so that growth rates were increased. T4 increased degradation rates so that there was no increased net growth in muscle or liver; in heart, T4 did induce increased growth despite the large increase in degradation rate. Tibial length was increased by both hormones; GH treatment of dwarf mice also increased cartilage sulphate incorporation on day 9, but T4 treatment did not, suggesting that bone growth is transient with T4 treatment.
Normal mice showed no changes in growth or tissue protein metabolism in response to GH, but following T4 treatment there was increased protein turnover due to higher tissue RNA concentrations, although only heart growth was increased. Thus normal mice showed almost no net response to GH or T4, but dwarf mice showed a large response to both hormones. The response was different, however, in that GH caused concomitant increases in growth rates whereas T4 altered body tissue proportions.
J. Endocr. (1988) 119, 31–41
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ABSTRACT
This study was designed to test the hypothesis that oestrogens inhibit growth by reducing hepatic somatomedin generation. We have attempted to deliver oestrogen preferentially to the liver by transplanting ovarian tissue into the spleen. Four groups of rats were compared: intact, ovariectomized, ovariectomized with successful ovarian transplants, and animals where due to adhesions between the transplant and body wall and/or viscera oestrogens reached the general circulation. Plasma levels of LH and FSH, uterine weights, ovarian weights and vaginal smears supported this classification of animals. Ovariectomy increased body weight, body length, bioassayable serum somatomedin levels and 35SO4 2− uptake into costal cartilage in vivo compared with intact rats and animals with adhesions. Preferentially exposing the liver to oestrogen did not suppress the increased growth, serum somatomedin activity or uptake of 35SO4 2− in vivo observed in ovariectomized animals. The results suggest that the presence of oestrogen in the general circulation is associated with growth suppression and lowered somatomedin bioactivity while the presence of oestrogen in the hepatic portal circulation has little effect on body growth. We conclude that oestrogen does not appear to inhibit growth in the rat by influencing the release of somatomedin from the liver. It also seems that serum somatomedin concentration may not reflect liver somatomedin generation but overall production throughout the body.
J. Endocr. (1984) 103, 43–47
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Hypopituitary dwarf mice (Snell's strain) were found to have much reduced levels of serum somatomedin when compared with normal mice (apparently normal members of the Snell strain). Treatment with bovine growth hormone, prolactin or thyroxine induced growth in these animals; this was accompanied in each case by increased levels of serum somatomedin (primarily somatomedin C). Growth hormone had a dose-dependent growth-promoting effect, but this was not reflected in dose-dependent increases in serum somatomedin levels. These results are in accordance with the concept that somatomedin is involved in the regulation of overall somatic growth, but it seems likely that other factors are also involved.
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ABSTRACT
Monoclonal antibodies of certain epitope specificity have been shown to produce a marked dose-dependent enhancement of the somatogenic and lactogenic activity of human GH (hGH). Two antibodies (EB1 and EB2), binding to distinct antigenic determinants and expressed on both hGH and human chorionic somato-mammotrophin (hCS), significantly enhanced the hGH-stimulated uptake of 35S-labelled sulphate into cartilage. Similarly, these antibodies enhanced the lactogenic activity of both hGH and hCS in the pigeon crop sac test. Two hGH specific monoclonal antibodies (QA68 and NA71), defining a further two epitopes, exhibited only modest enhancing or inhibitory activity in these assays, whereas the binding of certain combinations of monoclonal antibodies resulted in either reversal of enhancement or inhibition of hormone activity. Univalent antibody fragments derived from EB1 were as enhancing as the intact antibody indicating that bivalency dependent mechanisms were not involved in the phenomenon. Enhancing monoclonal antibodies were relatively poor inhibitors of 125I-labelled hGH binding to liver microsomal receptors, which is in contrast with their previously described property of potent suppression of hGH interaction with lymphoid cell receptors. It is tentatively concluded that 'restriction' of hormone binding to particular hGH receptors, relevant to somatic growth or lactogenic activity, may play a role in the enhancement phenomenon of hGH in vivo.
J. Endocr. (1986) 110, 381–388
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ABSTRACT
This work demonstrates that complexing hGH with monoclonal antibody EBl (MAB-EBl) can produce a striking potentiation of the somatogenic actions of hGH in vivo in Snell dwarf mice. In short-term experiments significant increases in cartilage metabolism and body weight were noted; these responses were dose-dependent for both MAB-EBl and hGH concentration. Increased growth was also observed in long-term experiments. In marmosets where MAB-EBl cross-reacts with endogenous GH, MAB-EBl alone enhanced the actions of endogenous GH. A new perspective may be necessary to incorporate these results into the current concept of antibody action.
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The growth-promoting effects of a partially purified preparation of somatomedin (12·7 units/mg) were compared with those of various doses of bovine GH (5, 20 and 80 μg/day) when injected into hypopituitary dwarf mice. Growth parameters studied were body-weight and tail-length velocities (calculated as the slope of a regression line fitted to daily measurements against time), uptake of 35SO2− 4 into costal cartilage in vivo and organ weights (heart, liver and kidney). In the first experiment somatomedin (6·4 units/day), bovine GH and 0·9% NaCl were injected once daily in a volume of 0·1 ml for 10 days. Treatment with bovine GH promoted a significant dose-dependent increase in body-weight and tail-length velocities and 35SO2− 4 uptake into costal cartilage in vivo. Somatomedin also promoted a significant increase in body-weight velocity and 35SO2− 4 uptake, both responses were between that observed with the lowest dose of bovine GH and control values. Somatomedin did not promote increase in tail-length velocity. Organ weights did not differ significantly between any of the treatment groups when expressed as mg/g body weight. In the second experiment somatomedin (a daily total of 21·6 units/day) and 0·9% NaCl were injected three times per day in a volume of 0·033 ml, bovine GH was again injected once daily in a volume of 0·1 ml, and the treatment period was 12 days. As in the first experiment all doses of bovine GH and somatomedin promoted a significant increase in body-weight velocity. These results are consistent with the somatomedin hypothesis.
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SUMMARY
Hypopituitary dwarf mice were found to have reduced levels of serum somatomedin-like activity compared with normal mice of the Snell strain. Treatment with bovine growth hormone for 3 and 7 days resulted in growth without significantly increased levels of serum somatomedin-like activity, as detected by in-vitro uptake of 35SO4 2− into normal rat cartilage; only after treatment for 14 days was somatomedin activity significantly raised. However, treatment for 2 days with bovine growth hormone, bovine prolactin or thyroxine resulted in a dose-dependent increase in in-vivo uptake of 35SO4 2− into dwarf mouse costal cartilage; growth hormone and thyroxine did not act synergistically. Ten days of treatment with growth hormone promoted a dose-dependent increase in both growth (increased weight gain and tail length) and in-vivo uptake of 35SO4 2−. Increase in tail length was correlated with uptake of 35SO4 2−. Thus, in-vivo uptake of 35SO4 2− into dwarf mouse costal cartilage provides a sensitive method for detecting a dose-related effect of growth hormone.
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Serum from adrenalectomized rats was equipotent with serum from non-adrenalectomized animals when measured in a rat cartilage somatomedin bioassay. Extraction with butanol of sera from normal or adrenalectomized rats reduced their potency in the somatomedin bioassay rather than increasing it as has been previously reported. Butanol-soluble inhibitors of cartilage metabolism were found in sera from both normal and adrenalectomized rats. Cortisol and corticosterone, up to mildly supraphysiological levels, were found to have no effect on basal cartilage metabolism. These results suggest that physiological levels of glucocorticoids do not exert an inhibitory effect on the uptake of 35SO4 2− into immature rat cartilage. Since butanol-soluble inhibitors of cartilage metabolism were found in adrenalectomized rat serum it is unlikely that these substances are glucocorticoids.
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This paper presents an investigation into the effects of prolonged oestrogen treatment (20 days) on basal growth and on growth stimulated by GH in hypopituitary dwarf mice. Body 35SO4 2− weight and tail length were measured during the treatment period and uptake of S04 into costal cartilage in vivo at the end of the treatment period. This study confirmed that treatment with human GH promotes a dose-dependent increase in body weight, tail length and uptake of 35SO4 2− in vivo; there was a highly significant correlation between these responses. Treatment with oestrogen alone had no significant effect on any of the parameters measured. All groups receiving combined oestrogen and human GH treatment showed a significant increase in body weight and tail length compared with animals receiving the same dose of oestrogen alone. However, the increase in body weight and tail length was significantly less in animals given the highest dose of oestrogen plus human GH than that observed in animals treated with the same dose of human GH alone. Treatment with oestrogen had no significant effect on the uptake of 35SO4 2− stimulated by human GH. Possible mechanisms for the growth-inhibiting effects of oestrogens are discussed.
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ABSTRACT
The enhancing effect of bovine FSH monoclonal antibody (bFSH-MAb) on the gonadotrophic activity of FSH was investigated in dwarf mice using a uterine weight bioassay.
Increasing doses of bovine FSH (NIH-FSH-B1; 3.3, 10 or 30 μg/day) were administered for 5 days to dwarf mice (groups of five) with or without administration of a bFSH-MAb preparation (USDA-bFSH-MC28; 100 μg protein/day) which at a dilution of 1:15 000 bound 50% of 125I-labelled bFSH (USDA-bFSH-BP3). The bFSH, at the doses given, gave no increases in uterine weight; when, however, these doses were given with bFSH-MAb, significant (three- to four fold) increases in uterine weight resulted.
