Cushing's disease and basophilic microadenomas.
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Adenoma↗
Biomedical subjects
W H Daughaday
Publications and source records attributed to W H Daughaday.
Growth hormone hypersecretion and acromegaly.
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Acromegaly↗
Maintenance of serum somatomedin activity in hypophysectomized pregnant rats.
Pregnant female rats were hypophysectomized on the 14th day of pregnancy without fetal loss or premature delivery. Completeness of hypophysectomy was confirmed by measurements of serum growth hormone and prolactin. Serum somatomedin activities were measured by the hypophysectomized rat costal cartilage in vitro assay using a human serum standard. In this assay somatomedin activity of normal rat serum is about four times that of normal human serum. Forty-eight hours after hypophysectomy serum somatomedin was maintained at 3.9 +/- 1.0 units/ml. At this time after operation somatomedin activity of nonpregnant hypophysectomized rat serum would be virtually undetectable. Somatomedin concentrations were still maintained on the 18th and 20th day of pregnancy. However, within 24 hours after delivery somatomedin had fallen to less than 0.6 units/ml and by three days post delivery were less than 0.2 units/ml. These observations indicate that the fetal-placental unit, probably by secreting a chorionic somatomammotropin, can maintain the concentration of growth hormone-dependent somatomedin in tha absence of the pituitary.
Animals↗
Growth failure with normal serum RIA-GH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH.
Two three-year-old boys with dwarfism (height ages 1-4/2 and 1-11/12 years) and delayed bone ages (1-4/12 and 1-9/12 years) had normal growth hormone (GH) responses after stimulation and low levels of somatomedin. Unlike patients with Laron syndrome, the two patients generated normal levels of somatomedin after administration of exogenous hGH. Treatment with hGH (2 IU every other day) brought about a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment to 12 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 8.3 cm/year while on treatment. The two cases represent a new syndrome of dwarfism which may be caused by secretion of a biologically inactive but immunoreactive GH.
Child, Preschool↗
Extreme gigantism. Analysis of growth velocity and occurrence of severe peripheral neuropathy and neuropathic arthropathy (Charcot joints).
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Adolescent↗
Hormonal regulation of growth by somatomedin and other tissue growth factors.
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Dwarfism↗
Isolation of a somatomedin from plasma of rats bearing growth hormone secreting tumors.
We have purified a protein which has somatomedin-like properties from the serum of Wistar-Furth rats bearing a growth hormone producing pituitary tumor (MStT/W15). Activity was measured by a placental insulin and/or somatomedin C radioreceptor assay (SmC-RRA). The serum was initially filtered through Sephadex G-150 equilibrated with 0.1 M NH4HCO3 and 0.02% NaN3. On the G-150 column, radioreceptor insulin (RRI) and radioreceptor somatomedin C (RRSm-C) activities coincided and appeared predominantly in the 160,000 mol wt range with a minor proportion in the 50,000 mol wt range. The pooled active fractions were boiled for 30 min at pH 5.5. After removing denatured protein by centrifugation, the extract was passed through G-50 Sephadex equilibrated with 1% formic acid and 0.15 M NaCl. Sixty to 90% of the SmC-RRA activity in the effluent appeared in the 9000 mol wt range. This material has an isoelectric focusing range of 8.4--9.6, similar to that described for human somatomedin C. On SDS-urea polyacrylamide gel electrophoresis only one protein band was seen. The isolated peptide (rSm) stimulated sulfate uptake in hypophysectomized rat cartilage. The potency of two preparations was variously assayed from 14.0 to 54.7 units/mg. Rat somatomedin was iodinated and purified by absorption on and elution from placental membranes. Eight to 12% of rat [125I]Sm was specifically bound by human placental membranes. Rat [125I]Sm was displaced by hSmC and rSm and human NSILA-S, partially displaced by procine proinsulin and poorly displaced by rat insulin. In preliminary studies, rat [125I]Sm was displaced from receptors on human placental membranes by sera from pituitary tumor bearing rats greater than normal rat sera greater than hypophysectomized rat sera.
Animals↗
Characterization of a protein in mid-term human amniotic fluid which reacts in the somatomedin-C radioreceptor assay.
Amniotic fluid contains materials other than insulin which react in a somatomedin C radioreceptor assay using human placental membranes. The material in mid-gestational amniotic fluid which reacted with the somatomedin C radioreceptor assay eluted slightly after albumin from a Sephadex G-150 column equilibrated with 0.1M NH4HCO3. Neither boiling nor treatment of this fraction with 1% formic acid yielded small molecular weight somatomedin-like peptides. Separation of the somatomedin reactive material (Sm RM) from albumin was achieved by gel filtration through Ultrogel AcA44 in 3.1M NH4HCO3. The active product had an apparent molecular weight of 33,000 to 35,000 Daltons; its isoelectric point determined by focusing was between 4.1 and 5.1. The purified amniotic fluid protein displaced somatomedin C in the somatomedin C radioreceptor assay but did not compete with insulin in the insulin radioreceptor assay. Sm RM produced only a slight stimulation of thymidine uptake in human fibroblasts but was inactive in stimulating sulfate uptake in hypox rat costal cartilage. In human fibroblast cultures Sm RM inhibited the stimulation of thymidine uptake induced by human serum and by purified rat somatomedin. When Sm RM was added to the 125I somatomedin C, some of the radioactivity eluted from gel filtration at pH 8.6 was converted to a molecular weight complex of about 43,000. We conclude that the material which we have isolated from mid-gestational amniotic fluid is a protein which may bind somatomedin and make it unavailable to the somatomedin receptor of human placenta and human fibroblasts.
Amniotic Fluid↗
Adrenergic modulation of growth hormone secretion in acromegaly: alpha- and beta-adrenergic blockade produce qualitatively normal responses but no effect on L-dopa suppresion.
The serum GH response to oral L-Dopa during the separate infusions of saline, phentolamine and propranolol was exmined in 12 acromegalic patients. In six L-Dopa responsive patients, serum GH concentrations rose during propranolol infusions (and fell during phentolamine infusions as previously reported). There was no effect of propranolol or phentolamine on the fall in serum GH following oral L-Dopa in this group of patients. Thus, beta-adrenergic, as well as alpha-adrenergic, mechanisms are involved to the regulation of GH secretion in a qualitatively normal fashion in some acromegalic patients. However, the qualitatively abnormal suppressive effect of L-Dopa on GH secretion seen in some acromegalic patients does not appear to be mediated through either alpha-adrenergic or beta-adrenergic mechanisms.
Acromegaly↗
Altered responsiveness to hypophysiotrophic hormones of perifused rat pituitary tumours.
Since growth hormone (GH) and prolactin (Prl) secretion by human pituitary tumours is often influenced by the hypophysiotrophic hormones thyrotrophin-releasing hormone (TRH) and somatostatin (SRIF), we have examined the responses of several transplantable rat pituitary tumours to these substances in a perifusion apparatus. The MStT/W15 tumour did not alter its secretion of GH and Prl in response to TRH, SRIF, or a partially purified porcine hypothalamic extract containing GH-releasing activity; normal rat pituitaries show clear responses to each of these substances. Theophylline and dibutyryl cyclic AMP each provoked increased GH and Prl release from the tumour. A second specimen of the MStT/W15 tumour and a specimen of the MStT/W5 tumour behaved in a manner identical to the original MStT/W15, showing no response to TRH or SRIF, but releasing both GH and Prl when theophylline or dibutyryl cyclic AMP was given. The MtT/F4 tumour increased its secretion of GH in response to TRH, 10 mug/ml, and theophylline, but no effect was seen with lower concentrations of TRH or with SRIF; Prl secretion by the F4 tumour was increased by theophylline, but TRH and SRIF had no effect. The autonomy demonstrated in these experimental tumours may be due to a loss of specific hypophysiotrophic hormone receptors or of secretory activating mechanisms.
Animals↗
Pituitary regulation of human growth hormone binding sites in rat liver membranes.
We have studied the binding of 125I-human growth hormone (hGH) to crude 100,000 X g membrane preparations from rat liver, and have studied factors which might regulate the capacity and affinity of hGH binding sites. Membrane preparations have livers of pregnant rats bound between 8% and 18% of the 125I-hGH initially added, and 70%-80% of that bound was displaced by 1 mug of unlabeled hGH. Humans prolactin (hPrl) displaced 125 I-hGH in a manner parallel to hGH itself but with about one-third the potency. Ovine, porcine, and rat Prl, and rat and bovine GH were much less effective. Scatchard analysis of specific hGH binding by a variety of different rat liver membrane preparations revealed a single order of binding site in each case with a binding affinity of 0.93-1.62 X 10(-9) M-1. Membranes from pregnant rats had twice the binding capacity of membranes from nonpregnant female rats, and about six times the capacity of sites present in preparations from normal adult male rats and hypophysectomized (Hx) male or female rats. Female or male rats with extremely high circulating GH an Prl levels, due to the presence of transplantable GH/Prl secreting pituitary tumors showed a significantly greater binding capacity than did the pregnant rats. Estradiol (E2) treatment (25 mug/day for 10-12 days) of normal male rats led to an increase in specific hGH binding. Treatment of hypophysectomized male rats with bovine GH (100 or 500 mug/day) +/- E2 (25 mug/day) for 5-10 days stimulated both body weight gain and the incorporation of sulfate by cartilage from the treated rats, but no significant increase was observed in the characteristics of 125I-hGH binding. These results indicate that high levels of E2, GH, and/or Prl play an important role in the regulation of hGH binding sites in rat liver membranes. The restoration of binding sites in liver from hypophysectomized rats, however, apparently requires additional factors which are as yet unidentified. The role of the hGH binding sites in the physiologic actions of GH also remains to be determined.
Animals↗
Comparison of somatomedin activity in perfusates of normal and hypophysectomized rat livers with and without added growth hormone.
We compared the somatomedin (SM) activity of perfusates of livers from normal and hypophysectomized (hypox) rats with and without the addition of growth hormone (GH) to the perfusions. Livers were perfused for a total of 3 hours, with a change of Waymouth's medium MB 752/l every 30 min, in a continously recirculating system. SM activity was estimated by the stimulation of the incorporation of sulfate by hypox rat costal cartilage incubated in vitro. Endogenous SM activity (no addition of GH) in the perfusates of the livers of normal rats was initially 136 +/- 17% above buffer levels (mean +/- SE) and fell gradually to near-buffer levels over the first 2 1/2 hours. Endogenous SM activity in the perfusates of livers from hypox rats was initially 72 +/- 10% above buffer levels, significantly lower than that of the normal livers, and reached buffer levels with the fifth medium change. Pretreatment of hypox rats with GH in vivo increased their initial liver perfusate SM activity to 134 +/- 25%, comparable to that of normal livers and significantly greater than that of livers of untreated hypox rats. The addition of GH (25 mug/ml) to the perfusion of both normal and hypox rat livers led to significant increases in perfusate SM activity compared with that of control perfusates at the same time periods. The increase in SM activity was not significant until after 0-30 minutes with hypox livers, and after 30-90 minutes with normal livers. Although it has previously been reported that the direct addition of GH to livers perfusion systems led to an increase in perfusate SM activity, we have now established that in the absence of added GH, perfusates of normal rat livers contain significant SM activity, and that perfusates of normal rat livers contain more SM activity than perfusates of hypox rat livers. In addition, the observation that GH pretreatment increases the SM activity of perfusates of hypox rat livers constitutes the first evidence that SM activity of any body tissue may be altered by administration of GH in vivo.
Animals↗
The effects of insulin and growth hormone on the release of somatomedin by the isolated rat liver.
Livers from hypophysectomized (hypox) rats were perfused with oxygenated Waymouth's medium in a system which permitted continuous recirculation for separate 30 minute periods after which fresh medium was supplied. In most experiments 6 changes of medium were carried out over a 3 hour period. The somatomedin activity of each perfusate was determined by measuring its ability to stimulate sulfate uptake in hypox rat cartilage in vitro. For comparison between experiments the results are expressed as the per cent stimulation of sulfate uptake by the perfusate compared with the unperfused buffer. Without hormonal additions there was a progressive fall in the release of somatomedin activity during the 6 periods of study. When compared with the results without hormone, the addition of 1000 muU/ml of insulin per ml of medium during the 2nd to 6th period led to a significant increase in perfusate somatomedin activity at all periods. The addition of 100 muU/ml of insulin was without significant effect. The possible inter-relationship between insulin and growth hormone in the regulation of somatomedin release was studied with a dose of bGH of 250 ng/ml which had previously been shown to be insufficient by itsel to stimulate somatomedin release. When added to a medium containing 1000 muU/ml of insulin, this dose of bGH did not significantly stimulate somatomedin release beyond that obtained with insulin alone. However, when 250 ng/ml was added to a medium containing 100 muU/ml insulin, a significant stimulation of somatomedin release was observed while the addition of each hormone separately was without significant effect. These results support the hypothesis that insulin shares with GH the regulation of somatomedin release by the liver. Differences in insulin concentration may explain some clinical situations in which somatomedin concentrations cannot be correlated with GH levels.
Animals↗
Craniopharyngioma: the role of insulin in promoting postoperative growth.
To elucidate the mechanism for growth following surgery in children with craniopharyngioma, serum somatomedin and prolactin levels, and plasma insulin (IRI) levels in response to oral glucose and intravenous tolbutamide, were determined in 5 and 8 children, respectively, at variable intervals following removal of the tumor. All patients had growth hormone (GH) deficiency following surgery. Seven of 8 children had normal growth (5 cm per year or greater) postoperatively for varying periods of time; 2 children continued to grow normally 6 and 8 years after surgery. Mean (+/- SE) somatomedin level was 0.78 +/- 0.1 U/ml (normal 0.4-1.5 U/ml). Serum somatomedin was normal in 4 children with normal postoperative growth and was also normal in a child who grew poorly. Mean (+/- SE) prolactin level was 6.9 +/- 3.3 ng/ml (normal 0-20 ng/ml). In 5 non-obese children with craniopharyngioma mean (+/- SE) peak IRI level was 104.4 +/- 24.4 muU/ml after oral glucose and 56.7 +/- 8.4 muU/ml after intravenous tolbutamide. These values are similar to mean (+/- SE) peak IRI levels following glucose and tolbutamide in normal children, and significantly higher (P less than 0.05) than those of idiopathic hypopituitary children. In 2 obese children with craniopharyngioma peak IRI levels were 255 and 107 muU/ml after glucose and 208 and 103 muU/ml after tolbutamide, respectively. The patient with suboptimal growth had low IRI responses to stimuli similar to hypopituitary children. Although there was a significant correlation between peak IRI levels following glucose (r = 0.63, P less than 0.025) and tolbutamide (r = 0.75, P less than 0.01) and the rates of growth of the combined data from obese and non-obese patients, no correlation was found between the growth rates of only the non-obese craniopharyngioma patients and their peak IRI levels. No significant correlation was found between mean somatomedin level and mean rate of growth. Normal postoperative growth in all children with craniopharyngioma was associated with normal serum somatomedin activity and pancreatic beta-cell responsiveness to stimuli despite GH deficiency. The results suggest that insulin may be important in the control of somatomedin and growth in these children.
Antigens↗
Receptor-active growth hormone in Laron dwarfism.
The hepatic radioreceptor assay for hGH has been applied to the detection of hGH in the sera of patients with high growth hormone dwarfism (Laron dwarfism). Substantial quantities of receptor-active hGH were found in the sera of all 7 patients studied. In one patient, arginine infusion elicited a prompt increase in both immunoactive and receptor-active hGH. These observations suggest that circulating hGH in Laron dwarfism is biologically active and support the concept that the disease may be caused by a generalized defect in hGH receptors.
Arginine↗
Amniotic fluid reactivity detected by somatomedin C radioreceptor assay: correlation with growth hormone, prolactin and fetal renal maturation.
Amniotic fluid was assayed by a radioreceptor assay utilizing 125I-somatomedin C and placental membranes. Growth hormone and prolactin levels were measured by radioimmunoassay at different gestational ages (8-41 weeks). Somatomedin receptor activity, growth hormone, and prolactin reached high levels during early gestation (8-26 weeks) displaying different patterns of appearance which reflect fetal serum levels of these hormones. After 26 weeks gestation all these hormones decreased in concentration. This decrease showed a strong correlation with fetal renal maturation as measured by amniotic fluid creatinine levels.
Amniotic Fluid↗
Factors governing the stimulation of embryonic chick cartilage by somatomedin.
In these studies of the stimulation of embryonic chick pelvic rudiments by somatomedin (Sm) in serum, we have found that cartilage weight and duration of cartilage exposure to serum determine the stimulation of cartilage by serum and the relative stimulation by Sm and by other non-Sm serum components, respectively. These factors are critical for the use of this system to measure Sm in serum. Initial experiments revealed that incorporation of sulfate (SO4) by cartilage incubated in buffer fell rapidly after 9 h and reached very low levels by 30 h. Incubation in 40% normal human serum (NHS) produced significant stimulation of incorporation of SO4 after 4 h, and maintained at least initial levels of incorporation for 24 h. The greatest % stimulation by NHS over buffer was seen with prolonged incubation (44 h). However, specificity for Sm (iscrimination between NHS and hypophysectomized human serum (HHS)) was greater with shorter incubation times. The potency of HHS was 11, 42 and 92% of the potency of NHS following early, intermediate and late measurement of incorporation of SO4 by cartilage, respectively. The best overall results were obtained with intermediate incubation time and measurement of SO4 incorporation ((35S)-SO4 present for the final 5 h of a 25 h incubation), which allowed good precision (gamma = 0.17) while maintaining satisfactory specificity for Sm. Since prolonged incubation with late measurement of SO4 incorporation allowed the greatest % stimulation by serum with little differentiation between NHS and HHS, stimulation of incorporation of SO4 under these conditions is apparently due to non-Sm factors present in both NHS and HHS. In addition to incubation time, cartilage stimulation by serum was also determined by cartilage weight. Lighter cartilage (from younger embryos) was associated with higher unstimulated incorporation of SO4 (P less than 0.01), lower stimulation by added serum (P less than 0.01), and inadequate assay precision (P less than 0.05): satisfactory assays were generally obtained with cartilage rudiments weighing more than 0.7 mg (dry weight).
Animals↗
Current concepts of somatomedin and other biologically related growth factors.
Since the discovery 20 years ago that the growth-promoting effects of somatotropin are mediated through a serum factor(s), research in this area has rapidly expanded. It is the purpose of this review to bring this area of scientific endeavor into perspective. The first part of this review will deal with aspects of total serum somatomedin activity and its biologic actions and measurements in health and disease. The last part of this review will summarize some of the physical and biologic characteristics of the recently purified "somatomedin-like" substances: somatomedin A, B, and C, NSILA-S (nonsuppressible insulin-like activity-soluble in acid ethanol) and MSA (multiplication-stimulating activity).
Acromegaly↗