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Search for other papers by A. N. Brooks in
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Search for other papers by A. White in
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ABSTRACT
In sheep, birth is preceded by an increase in fetal plasma concentrations of ACTH and cortisol. Activation of the fetal pituitary-adrenal axis is pivotal to the onset of parturition in this species and may be regulated, at least in part, by corticotrophin-releasing factor (CRF). Pulsed administration of CRF has been shown to activate the fetal pituitary-adrenal axis in immature fetal sheep. However, pituitary ACTH responsiveness declined after continued administration of CRF, as a result of increasing negative feedback effects of increased concentrations of endogenous cortisol. To test the hypothesis that arginine vasopressin (AVP) is required, in addition to CRF, to produce the necessary trophic stimulus to the pituitary-adrenal axis, we administered saline, CRF (1 μg), AVP (200 ng) or CRF plus AVP as pulses every 4 h for 7 days to fetal sheep beginning at days 117–120 of pregnancy (term =145 days). Pituitary-adrenal responses were assessed by measuring plasma concentrations of immunoreactive (ir) ACTH and cortisol in response to one of the pulses on each of the 7 days of treatment.
On day 1, CRF and AVP significantly increased plasma concentrations of ir-ACTH and there was a synergistic interaction when the two peptides were given together (P<0·05). However, as pulsed treatment continued there was a decline in the pituitary ir-ACTH response to all treatments (P<0·05). This decline in pituitary response occurred over a much longer period of time when CRF and AVP were given together when compared with the two peptides given separately. In contrast, the cortisol response to endogenously released ir-ACTH after administration of CRF, AVP or CRF plus AVP was small on day 1 but gradually increased as treatment progressed. This was particularly apparent when the two peptides were given together. A significant inverse correlation (r = 0·781, P<0·01) between basal cortisol concentrations and the ir-ACTH response to CRF plus AVP was observed over the 7 days of treatment. Premature delivery was not induced by any of the treatments despite significant increases in fetal adrenal weight. Furthermore, there were no changes in the circulating maternal plasma concentrations of progesterone or oestrone during the 7 days of the experiment.
We conclude that combination of CRF and AVP administered as pulses to immature fetal sheep results in a greater degree of pituitary-adrenal activation when compared with the two peptides given independently. However, even after this combined treatment regimen pituitary responsiveness eventually declines, an effect which may be due to increased negative feedback effects of increased endogenous cortisol.
Journal of Endocrinology (1990) 124, 27–35
Search for other papers by S. L. JEFFCOATE in
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Search for other papers by N. WHITE in
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SUMMARY
Hypothalamic extracts from three mammalian species (rat, rabbit and sheep) were found to contain several ng of immunoreactive thyrotrophin releasing hormone (TRH)-like activity. This substance chromatographed on ion exchange chromatography (carboxymethyl cellulose) as a single peak that was indistinguishable from synthetic TRH. Hypothalamic TRH was also inactivated by normal human plasma at a rate (1·21–1·46%/μl plasma/h and 1·59–1·77%/50 μl plasma/min) similar to that of synthetic TRH (1·42%/μl plasma/h and 1·73%/50 μl plasma/min). This combination of chromatographic and enzymic techniques can be applied to the identification of immunoreactive TRH in body fluids.
Search for other papers by R. N. MURDOCH in
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Search for other papers by I. G. WHITE in
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SUMMARY
The activity of several enzymes has been measured in the uterine endometrium of the rabbit during oestrus and pseudopregnancy and after injecting oestradiol benzoate or progesterone 28 days after ovariectomy. The enzyme activity of the uterine fluid has been determined during oestrus and the effect of uterine ligation studied.
Progesterone and the induction of pseudopregnancy stimulated succinic dehydrogenase (SDH) and glucose-6-phosphate dehydrogenase (GDH) activity and depressed amylase and lactic dehydrogenase (LDH) activity. In ovariectomized does, glutamate-oxaloacetate transaminase (GOT) activity increased after the injection of progesterone. Progesterone also stimulated endometrial phosphatase after ovariectomy but, when given after a period of oestrogen treatment, it limited the even greater response of acid and alkaline phosphatase to oestrogen; the activity then attaining the same level as when progesterone alone was given.
SDH, GDH and glycerylphosphorylcholine (GPC) diesterase could not be detected in uterine fluid but amylase and alkaline phosphatase were in greater concentration than in the endometrium. GPC diesterase was, however, found to be present in uterine tissue. Ligation of the uterus did not significantly alter the enzyme activity of the endometrium.
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Search for other papers by M. C. White in
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In 1971 Midgeley & Jaffe published data suggesting that the plasma concentration of gonadotrophins in normal women varied in a pulsatile fashion. This observation has been confirmed subsequently and considerable effort has been directed at defining the nature and origin of the pulsatile pattern of gonadotrophin secretion in the normal and abnormal ovarian cycle. Results of these studies have shown that systemic pulses of luteinizing hormone (LH) appear to be the consequence of pulsatile stimulation of the gonadotroph by LH-releasing hormone (LHRH) in the pituitary portal capillary system (Clarke & Cummins, 1982). The major source of this pulsatile release of LHRH is the arcuate nucleus of the mediobasal hypothalamus, which is in turn controlled by higher centres in the brain. This electrophysiological control mechanism is modified by a number of factors, such as noradrenaline, endorphin and vasoactive intestinal peptide, all of which have been shown to alter the LH pulse
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Search for other papers by N. White in
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Search for other papers by S. L. Jeffcoate in
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ABSTRACT
Oestrogen-2/4-hydroxylase activity was measured in whole brain, thalamus, amygdala, hypothalamus and pituitary gland of lactating rats and in whole brain of rats on different days of the oestrous cycle. Enzyme activity was increased in whole brain and in each of the brain regions examined (with the exception of the amygdala) in lactating rats. This increase in enzyme activity was associated with an increase in serum prolactin levels. During the oestrous cycle, enzyme activity in whole brain was higher on metoestrus and dioestrus than on pro-oestrus and oestrus. The decrease in enzyme on pro-oestrus was associated with an increase in both serum oestradiol and prolactin levels. These results are consistent with the hypothesis that changes in oestrogen-2/4-hydroxylase activity are associated with changes in prolactin and oestradiol secretion and may play a regulatory role in reproduction.
J. Endocr. (1985) 107, 191–196
Search for other papers by S. L. JEFFCOATE in
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The ability to assay small amounts of the peptide releasing hormones in biological fluids would aid greatly in the assessment of hypothalamic function. We have recently described a specific radioimmunoassay for luteinizing hormone releasing hormone (LH-RH) (Jeffcoate, Fraser, Gunn & Holland, 1973a, b) and in this study we report a radioimmunoassay for the tripeptide, thyrotrophin releasing hormone (TRH).
Thyrotrophin releasing hormone (2 mg) was conjugated to 10 mg bovine serum albumin in borate buffer pH 9·0 by the bis-diazotized benzidene method (Bassiri & Utiger, 1972 a). After 2 h at 5 °C the mixture was dialysed against distilled water for 48 h and against 0·15 m-NaCl for 24 h. This technique conjugates TRH by the imidazole ring of histidine to the protein. A sample of conjugate (2·5 mg) in saline was homogenized with Freund's complete adjuvant and injected into 20 intradermal sites in a White New Zealand rabbit.
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Search for other papers by N. White in
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Search for other papers by S. L. Jeffcoate in
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ABSTRACT
Catecholoestrogens are naturally occurring metabolites of oestrogens which are found in brain tissue and for which a neuroendocrine role has been postulated. However, reports of their effects on prolactin secretion are ambiguous and as yet no defined function has been attributed to them.
The effects of 2-hydroxyoestradiol (2-OHE2) and dopamine on the release of prolactin in vitro by perfused pituitary glands from normal adult female rats at different stages of the oestrous cycle have been investigated. The purity and stability of the 2-OHE2 preparation before and after exposure to pituitary tissue was confirmed by radioenzymatic assay and subsequent thin-layer chromatography. Dopamine (500 nmol/l, 100 nmol/l) was found consistently to suppress release by 60%; this effect was immediate and reversible upon removal of the dopamine. In contrast, the effects of 2-OHE2 (10 nmol/l, 100 nmol/l) were found to vary during the cycle. No effect on prolactin release was evident during either dioestrus or pro-oestrus, but during oestrus a similar, though less potent, suppression of prolactin secretion to that of dopamine was observed (35% suppression compared with controls).
The cyclical variation in the suppressive effect of 2-OHE2 on prolactin secretion in the female rat is compatible with a postulated neuroendocrine role for this catecholoestrogen.
J. Endocr. (1986) 111, 199–204
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Search for other papers by E. C. GRIFFITHS in
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Search for other papers by K. C. HOOPER in
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SUMMARY
The TRH-degrading activity of rat serum in vitro is five times more potent than that of human serum. In rats, it is significantly reduced in hypothyroidism (thiouracil-induced) and significantly increased in hyperthyroidism (T3 or T4-induced). This suggests a possible role in the regulation of adenohypophysial-thyroid function which is probably, in turn, dependent on thyroid hormone, rather than TSH, levels.
Faculty of Medical and Human Sciences, Faculty of Life Sciences, Diabetes Research Group, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill Building, Manchester M13 9PT, UK
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Faculty of Medical and Human Sciences, Faculty of Life Sciences, Diabetes Research Group, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill Building, Manchester M13 9PT, UK
Search for other papers by A White in
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Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic α-cells, but is cleaved to glucagon-like peptide-1 (GLP-1) by PC1 in intestinal L-cells. The aim of this study was to identify mechanisms which switch processing of proglucagon to generate GLP-1 in the pancreas, given that GLP-1 can increase insulin secretion and β-cell mass. The α-cell line, αTC1-6, expressed PC1 at low levels and GLP-1 was detected in cells and in culture media. GLP-1 was also found in isolated human islets and in rat islets cultured for 7 days. High glucose concentrations increased Pc1 gene expression and PC1 protein in rat islets. High glucose (25 mM) also increased GLP-1 but decreased glucagon secretion from αTC1-6 cells suggesting a switch in processing to favour GLP-1. Three G protein-coupled receptors, GPR120, TGR5 and GPR119, implicated in the release of GLP-1 from L-cells are expressed in αTC1-6 cells. Incubation of these cells with an agonist of TGR5 increased PC1 promoter activity and GLP-1 secretion suggesting that this is a mechanism for switching processing to GLP-1 in the pancreas. Treatment of isolated rat islets with streptozotocin caused β-cell toxicity as evidenced by decreased glucose-stimulated insulin secretion. This increased GLP-1 but not glucagon in the islets. In summary, proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by elevated glucose, activation of TGR5 and β-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect β-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.
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Interactions between pro-opiomelanocortin (POMC)-derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken comprehensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived peptides endogenously secreted within the hypothalamus, (2) to investigate the potency of AGRP(83-132) antagonism with respect to each POMC-derived peptide and (3) to determine whether AGRP(83-132) and POMC-derived peptides act allosterically or orthosterically. We have found that beta melanocyte-stimulating hormone (betaMSH), desacetyl alpha MSH (da-alphaMSH) and adrenocorticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, alphaMSH. Moreover, even MSH precursors, such as beta lipotrophic hormone, showed significant binding and functional activity. Therefore, many POMC-derived peptides could have important roles in appetite regulation and it seems unlikely that alphaMSH is the sole physiological ligand. We have shown that AGRP(83-132) acts as a competitive antagonist. There was no significant difference in the potency of inhibition by AGRP(83-132) or agouti(87-132) at the MC4-R, regardless of which POMC peptide was used as an agonist. Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects. This provides strong pharmacological evidence that AGRP(83-132) acts orthosterically at the MC4-R to inhibit Gs-coupled accumulation of intracellular cAMP.
