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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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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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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 patterns of secretion of GH, LH, FSH and prolactin were determined over a single night (20.00–08.00 h; 15-min sampling) in 34 normal subjects (17 male, 17 female, aged 9·1–20·9 years). Plasma GH was measured by an immunoradiometric assay and LH, FSH and prolactin by radioimmunoassay in all samples. Data were analysed by Fourier transformation and cross-correlation after stationarization.
The highest mean GH levels were noted in girls at Tanner stage 2/3 and in boys at stages 4/5. Prolactin levels were highest in girls at stage 4/5 and in boys at stage 2/3. LH and FSH showed a progressive rise by puberty stage in both sexes. The dominant pulse periodicities of GH and prolactin were 150–180 min in girls and 180 min in boys. LH and FSH pulse periodicity was around 90 min in early puberty and 180 min in later puberty in both sexes. LH and prolactin pulses showed a phase relationship with GH with a lag of 30–75 min (r = 0·32; P < 0·001) and 30 min (r = 0·47; P < 0·0001) respectively. Generally, LH and prolactin pulses were in phase (r = 0·42; P < 0·0001) and there was a highly significant correlation (r = 0·64; P < 0·0001) between FSH and LH pulsatility.
Whereas mean overnight concentrations and pulse periodicity of the principal pituitary hormones varied between the sexes during early puberty, by the end of puberty a dominant pulse periodicity of around 150–180 min was established and there was remarkable temporal coupling of pulsatility.
Journal of Endocrinology (1991) 130, 141–149
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ABSTRACT
Human somatomedin C has been purified from Cohn fraction IV paste by a simplified procedure using chromatofocusing, hydroxylapatite chromatography and reverse-phase high performance chromatography. The purified material has a specific activity by somatomedin C radioimmunoassay of 9160 units/mg (1 unit is defined as the amount of somatomedin present in 1 ml normal adult male human serum), representing a 650 000-fold purification, and possesses sulphation, mitogenic and insulin-like activities (specific activities of 3388 units/mg, 832 units insulin equivalents/mg and 1122 units/mg respectively). Somatomedin C is shown to be a potent stimulator of DNA synthesis (50% maximum stimulation at 150 fmol/ml) in isolated chondrocytes derived from costal cartilage, a major physiological target tissue.
J. Endocr. (1986) 110, 151–158
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Changes in the rate of in-vitro degradation of thyrotrophin releasing hormone (TRH) in serum as related to age have been investigated in the rat and man. In rats, no inactivation was found up to the age of 15 days but thereafter an age-related increase in inactivation was detected with approximately 75% inactivation in 60 min at 40 days and reaching a maximum of 88–93% inactivation in adult male and female animals. The human serum samples studied (both male and female) showed a similar but less clear-cut pattern of inactivation of TRH compared with that found in the rat. A physiological role for these age-related changes in the degradation of TRH remains to be established but it has been concluded that the changes observed in both rat and man may be associated with growth and development, possibly by facilitating feedback control of thyrotrophin secretion through the degradation of TRH.
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The incorporation of [3H]thymidine by rat costal cartilage in vitro was studied at different fetal and postnatal ages and the effect of partially purified human somatomedin, mouse epidermal growth factor, platelet secretion products, insulin and growth hormone on thymidine uptake by fetal cartilage was examined. Thymidine uptake in plasma-free medium was many times greater in late fetal life than after birth. The incorporation of [3H]thymidine into costal cartilage from 21-day fetuses was significantly (P <0·05) increased above control values in the presence of 10 μg somatomedin/l, and when cartilage was incubated in medium containing somatomedin and diluted human plasma there was a synergistic action. Epidermal growth factor at a concentration of 1 ng/l was a potent stimulator of thymidine uptake. Secretion products from human platelets after their aggregation by thrombin stimulated [3H]thymidine uptake at a concentration of 2% (v/v), but were inhibitory at high concentrations. High concentrations of platelet secretion products stimulated the incorporation of [35S]sulphate by cartilage. A pharmacological concentration of 10 mu. insulin/ml stimulated [3H]thymidine uptake, but not concentrations of 1 or 100 mu./ml. Growth hormone had no effect. The results showed that fetal cartilage had a greater endogenous mitogenic activity than postnatal cartilage. While somatomedins may be important in the regulation of fetal body growth, other protein growth factors also stimulate fetal skeletal tissues.
