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Abstract
Changes in thyroid status have a major effect on the GH/insulin-like growth factor (IGF) axis. The majority of IGF in the circulation is bound to specific IGF-binding proteins (IGFBPs) of which six have been cloned and sequenced. We have studied changes in hepatic gene expression of IGFBP-1, -2 and -3, in male Wistar rats rendered hyperthyroid (thyroxine, 200 μg/kg per day) or hypothyroid (propylthiouracil, 0·1% daily). Littermates of the same age were used as controls (n=6 in each group). Thyroxine was measured by radioimmunoassay, and hepatic IGFBP-1, -2 and -3 mRNA levels by Northern blot analysis using specific rat cDNA probes with a 28S ribosomal probe as a loading control. Mean± s.e.m. thyroxine levels were 247·0±44·5 (hyperthyroid group), <9·0 (hypothyroid group) and 76·0 ± 4·5 nmol/l (control group). IGFBP-1 and -2 mRNA levels in the hypothyroid animals compared with the controls were significantly increased, but similar levels of expression were found in thyrotoxic and control rats. IGFBP-3 mRNA levels in hypothyroid animals were decreased, and increased in thyrotoxic animals. Thus, in the adult rat, hypothyroidism is associated with increased hepatic IGFBP-1 and -2 gene expression, but decreased IGFBP-3 gene expression, while in thyrotoxicosis there are normal IGFBP-1 and -2 mRNA levels but increased IGFBP-3 gene expression. These results suggest that there is specific and different transcriptional regulation for IGFBP-1, -2 and -3 in hypoand hyperthyroid rats.
Journal of Endocrinology (1994) 140, 251–255
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SUMMARY
In a case of hydatidiform mole accompanied by theca lutein cysts there was a greatly increased urinary excretion of pregnanetriol. Incubation of the mole tissue with [4-14C]pregnenolone resulted in the formation of 17α-hydroxypregnenolone, progesterone, 16α-hydroxyprogesterone and 16βhydroxyprogesterone.
Cholesterol, pregnenolone, 17α-hydroxypregnenolone, pregnanediol, pregnanetriol and androstenedione were isolated from both the mole tissue itself and from the ovarian cyst fluid. Progesterone and 17α-hydroxyprogesterone were characterized only from the cyst fluid. Greater quantities of the metabolic intermediates between pregnenolone and pregnanetriol were isolated from the cyst fluid than from the mole tissue.
On the basis of these results it is concluded that although the mole tissue is active in steroid metabolism the increased urinary excretion of pregnanetriol is a function of the polycystic ovaries.
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The interaction of GH, interleukin (IL)-6 and glucocorticoids is likely to be important in regulating the GH-insulin-like growth factor (IGF)-I axis. The signalling cascades activated by GH and IL-6 appear to be very similar, as demonstrated by studies using overexpression of the receptor and other components of the Jak-Stat and mitogen-activated protein (MAP) kinase pathways. Here we show that the human embryonic kidney cell line 293 (HEK293) expresses GH and IL-6 receptors endogenously. To determine which specific pathways might be activated by the two cytokines, at physiological levels of all components, we studied GH and IL-6 mediated signal transduction both under basal conditions and in the presence of overexpressed receptors and Stat proteins. Our results suggest a receptor specificity of Jak2 for GH receptors, and Jak1 for IL-6 receptors. Stat activation in response to GH and IL-6 was determined by reporter gene induction. Both GH and IL-6 were able to induce the reporter gene containing the Stat5 responsive element (LHRE) but the IL-6 response appeared to be mediated mainly through Stat3 activation. In contrast, the reporter gene containing the Stat3 responsive element (SIE) was IL-6 specific. The levels of gene induction by GH and IL-6 were not altered by the co-stimulation with GH and IL-6, suggesting that there is little cross-talk at the Jak-Stat activation level between the two cytokines. Neither GH nor IL-6 activated the MAP-kinase responsive serum response element (SRE), unless GH receptors or gp130 were overexpressed. Transfection of Stat3 or Stat5 expression vectors enhanced the response to GH and IL-6. Stimulation with dexamethasone synergistically enhanced GH activation of the LHRE reporter gene but had no effect on the IL-6 activation of the same reporter or on the SIE reporter gene. Thus, our studies suggest that while each cytokine, GH and IL-6, may activate various members of the Jak-Stat pathway in overexpression studies, specific activation of Stat3 by IL-6 and of Jak2 and Stat5 by GH can be observed in HEK293 cells and that in this system the synergistic effect of dexamethasone appears specific for Stat5.
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The expression and localisation of mRNAs for 5 alpha reductase Type I (5 alpha R-I) and Type II (5 alpha R-II) isoenzymes in human benign prostatic hyperplasia (BPH) were investigated by RT-PCR and by in mini hybridisation (ISH) using digoxigenin labelled riboprobes. In addition, we also examined the isoenzymes mRNA expression in primary BPH cultures of separated stroma/fibroblast and epithelial cells to determine whether primary cultures are appropriate models in which to investigate 5 alpha R activity and regulation. The results demonstrated conclusively the presence of mRNA encoding both isoenzymes in all specimens so far examined. Additionally, the presence of a functional 5 alpha R-I and -II activity in BPH was confirmed by enzyme assays. ISH studies localised the mRNA expression to both the fibroblast/stromal component as well as the epithelial cells of the hyperplastic tissue. In the glandular regions the expression for both isoenzymes was particularly strong in the basal layers of the epithelium whereas mRNA expression in the secretory cells was less pronounced. Expression of 5 alpha R-I and -II mRNAs in fibroblast was on the other hand variable with high expression in some areas and little in others. These findings were supported by our primary culture experiments which demonstrated that both the fibroblast and epithelial cells maintain a capacity to express both isoenzymes in vitro. In the case of the fibroblast, the capacity to express the isoenzymes was maintained following the sequential passaging of the cells up to passage 6, after which the cells no longer expressed either isoenzyme.
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ABSTRACT
Measurements of (a) 17-hydroxyprogesterone (17-OHP) in blood collected onto filter paper after heel puncture by lancet and (b) steroid metabolites in random collections of urine, were made in human infants born from 25 weeks of gestation onwards. The concentration of 17-OHP in blood eluted from filter paper samples was inversely related to both gestational age and birth weight. In mature infants, 17-OHP concentrations fell rapidly soon after birth, whereas concentrations remained high over the first month of life in infants born earlier than 33 weeks of gestation. Sulphated urinary steroids were identified as having a 3β-hydroxy-5-ene structure and although the pattern of excretion was similar in mature and premature infants, significantly higher concentrations were found in the premature group. Steroid metabolites normally present when concentrations of circulating 17-OHP are increased due to 21-hydroxylase deficiency were not detectable in urine samples collected from infants born prematurely. Where direct comparison of 17-OHP in blood spots and urinary steroid metabolites was possible, the concentrations of 17-OHP in blood samples paralleled 3β-hydroxy-5-ene steroid metabolites in urine. The results suggest that a circulating cross-reacting 3β-hydroxy-5-ene steroid may be responsible for increased concentrations of 17-OHP in infants born prematurely. Increased concentrations of both 17-OHP in blood spots and steroid sulphates in urine were associated with stress in premature, but not in more mature, infants suggesting that in infants born prematurely postnatal stress may delay adrenal maturation.
J. Endocr. (1987) 112, 473–480
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ABSTRACT
A synthetic 29-amino acid analogue of human pancreatic GH-releasing hormone (GHRH(1–29)NH2) has recently been shown to stimulate the release of GH in normal subjects. We have studied the GH response to GHRH(1–29)NH2 in nine children irradiated for brain and nasopharyngeal tumours, who were not growing and were deficient in GH as assessed by insulin-induced hypoglycaemia. Serum GH rose in response to GHRH(1–29)NH2 in all the children, and in five the peak serum GH response was > 20 mu./l. The data suggest that when hypothalamo-pituitary irradiation results in GH deficiency, this is due to a failure of the synthesis or delivery of endogenous GH RH from the hypothalamus to the pituitary cells. It also suggests that it may be possible to treat such children using synthetic GHRH in place of exogenous GH.
J. Endocr. (1986) 108, 25–29
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Department of Chemical Endocrinology, University Medical Centre, 6500 HB Nijmegen, The Netherlands
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Gilthead sea bream (Sparus auratus L.) were fed a vitamin D-deficient diet for 22 weeks. Growth rate, whole body mineral pools and calcium balance were determined. Plasma parathyroid hormone-related protein (PTHrP) and calcitriol levels were assessed. Expression of mRNA for pthrp and pth1r was quantified in gills and hypophysis. Fish on vitamin D-deficient diet (D− fish) showed reduced growth and lower calcium turnover (calcium influx, efflux and accumulation rates decreased) and unaltered plasma calcium levels. Plasma calcitriol levels became undetectable, PTHrP levels decreased in the D− fish. In controls, a significant increase in plasma PTHrP level over time was seen, i.e. it increased with body mass. Relationships were found between plasma PTHrP and the whole body pools of calcium, phosphorus and magnesium, indicative of a role for PTHrP in bone development. Expression of pthrp and pth1r mRNA was down-regulated in the hypophysis of D−fish, whereas in gill tissue, pthrp and pth1r mRNA were up-regulated. We conclude that lower pthrp mRNA expression and plasma values in D− fish reflect lower turnover of PTHrP under conditions of hampered growth; up-regulation of pthrp mRNA in gills indicate compensatory paracrine activity of PTHrP during calcitriol deficiency to guarantee well-regulated branchial calcium uptake. This is the first report to document a relation between PTHrP and calcitriol in fish.
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Abstract
The liver plays a central role in the IGF-I axis producing the majority of circulating hormone and some of its binding proteins (IGFBPs). Cirrhosis of the liver is characterised by changes in IGF-I and IGFBPs associated with liver fibrosis and regeneration. We have studied steady state levels of mRNA for the genes in the IGF-I axis in normal and cirrhotic human liver, localised the most highly expressed gene, IGFBP-1, and measured circulating IGFBP-3 by radioimmunoassay (RIA), IGFBP-2 and IGFBP-3 by Western ligand blot (WLB), and protease activity for IGFBP-3 in cirrhotic patients. Messenger RNA for IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 was detectable by Northern blotting in normal and cirrhotic liver although there was considerable variation in expression. IGFBP-2 and IGFBP-3 tended to be more highly expressed in cirrhotic liver and IGFBP-1 was more highly expressed in normal liver, although there were no significant differences. In normal liver, in situ hybridisation localised IGFBP-1 to hepatocytes. In cirrhotic liver the regenerating nodules showed expression of IGFBP-1 while there was none in fibrotic tissue. Circulating IGFBP-3 levels were low as measured by RIA and WLB but protease activity was only found in one patient. IGFBP-2 levels, assessed by WLB, were similar to the normal serum pool. Our data show that key mRNAs involved in the IGF-I axis continue to be expressed in cirrhotic liver despite end stage liver disease. The low levels of IGFBP-3 do not appear to be due to reduced gene transcription or increased protease activity.
Journal of Endocrinology (1996) 149, 209–216
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ABSTRACT
The damara mole rat, Cryptomys damarensis, is a strictly subterranean dwelling herbivorous rodent that in its natural habitat has no access to any obvious source of cholecalciferol (D3). We examined the effects of D3 supplementation, at physiological and supraphysiological doses, on calcium metabolism, plasma concentrations of calcium and alkaline phosphatase (ALP) and D3 metabolites. Animals not receiving a D3 supplement maintained normal plasma calcium concentrations. In addition, they exhibited a high apparent fractional mineral absorption efficiency (91%) and maintained a positive mineral flux. The serum concentration of 25-(OH)D3 was undetectable (< 5 nmol/l) and that of 1,25-(OH)2D3 was 41±10 pmol/l. Supplementation at a physiological dose of D3 resulted in increased plasma concentrations of D3 metabolites, food intake, apparent fractional absorption efficiency and apparent fractional retention efficiency. Despite the 1·8-fold increase in food intake, body mass remained constant suggesting that the enhanced energy intake was dissipated in catabolic processes. Plasma calcium and ALP concentrations were not significantly altered with physiological doses of D3. The group given supraphysiological doses of D3 exhibited hypercalcaemia, increased creatinine concentrations and markedly increased ALP levels. These data indicate that a pathological response to D3 intoxication occurred and that hepatic and renal excretory functions were impaired. It appears, therefore, that these animals function optimally at the low concentrations of D3 metabolites found naturally. Supplementation at both physiological and supraphysiological doses of D3 may disadvantage the damara mole rat.
Journal of Endocrinology (1991) 131, 197–202
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ABSTRACT
We have assessed the feasibility of screening newborn babies for congenital adrenal hyperplasia (CAH) by the direct measurement of 17-hydroxyprogesterone (17-OHP) in blood spots collected on filter paper (Guthrie cards) for the phenylketonuria, hypothyroidism and galactosaemia screening programmes run in Scotland. The procedure described for CAH uses an iodinated 17-OHP tracer and a specific 17-OHP antiserum sheathed within semipermeable nylon microcapsules. The method does not require a solvent extraction step, is inexpensive, precise, efficient and, therefore, practical for large-scale use. With this system the value of a neonatal screening programme was assessed in a retrospective analysis and a prospective trial.
The retrospective study of 15 paediatric cases of CAH illustrated that at least half were not diagnosed within 3 weeks of birth. Analysis of the original Guthrie card samples revealed increased levels of 17-OHP in all cases. The prevalence of CAH as calculated in the retrospective study was 1 in 20 907 with a range (within 95% confidence limits) of from 1 in 12 675 to 1 in 32 604 (n = 301 450). In the prospective trial a total of 92 051 consecutive samples was screened. Five cases of CAH were correctly identified with a current false positive rate of 0·042%. Analysis of urinary steroids confirmed defective adrenal 21-hydroxylase activity in all positive cases. In the prospective trial the prevalence was 1 in 18 401 with a range of from 1 in 7 422 to 1 in 50006.
We conclude that mass screening for CAH is both feasible and desirable.
J. Endocr. (1986) 108, 299–308
