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E. H. D. CAMERON, T. JONES, D. JONES, A. B. M. ANDERSON and K. GRIFFITHS

SUMMARY

As part of a continuing study of adrenal steroids in relation to breast cancer, various experiments were performed in order to study relationships between androgen and corticosteroid biosynthesis. Chopped tumour tissue from a 'mixed cell' adrenal adenoma (7·4 g.) removed from a patient in Cardiff Royal Infirmary was incubated with [4-14C]pregnenolone and [7α3H]17α-hydroxypregnenolone for periods of time ranging from 30 to 120 min. The results of this work suggest that 17α-hydroxyprogesterone may not be an obligatory intermediate in androgen or cortisol synthesis. Evidence from further experiments with 'normal' human adrenal tissue removed from breast cancer patients using previously established ultramicrochemical techniques indicates that dehydroepiandrosterone (DHA) sulphokinase enzyme system is confined to the zona reticularis of the gland. The conversion of [7α-3H]DHA sulphate, [7α-3H]androstenedione and [7α-3H]testosterone to oestrogens and their conjugates by adrenal homogenates was also investigated. Conversions were extremely low from all precursors.

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D. B. Jones, D. Marante, B. C. Williams and C. R. W. Edwards

ABSTRACT

The possible involvement of the lipoxygenase pathway of arachidonic acid metabolism in the events which take place during ACTH-induced stimulation of corticosterone secretion has been studied using an isolated rat adrenal cell system. Incubation with arachidonic acid resulted in an inhibition of ACTH-stimulated corticosterone production. The lipoxygenase pathway inhibitors nordihydroguaretic acid (NDGA), eicosatetraynoic acid (ETYA) and compound BW755C also produced inhibition of ACTH-stimulated corticosterone synthesis. The concentrations of the inhibitors at which 50% inhibition occurred were 15, 34 and 37 μmol/l respectively. The inhibitions produced by NDGA and ETYA were independent of cyclic AMP output. NDGA also inhibited corticosterone production induced by dibutyryl cyclic AMP but had no effect on corticosterone synthesis induced by pregnenolone.

Preincubation of adrenal cells with the lipoxygenase products 5, 12 and 15 hydroxyeicosatetraenoic acid (HETE) and with leukotrienes A4, B4, C4, D4 and E4 resulted in significant inhibitions of corticosterone production in response to ACTH with leukotriene A4 (LTA4) and with 15HETE and 5HETE. Conversely, incubation with glutathione (GSH), which is known to reduce intracellular LTA4 levels, produced stimulation (at 5 mmol GSH/1) and inhibition (at 50 mmol GSH/1) of corticosterone output. These studies suggest that the lipoxygenase pathway may be involved in ACTH-stimulated corticosterone synthesis.

J. Endocr. (1987) 112, 253–258

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D. B. Dunger, D. R. Matthews, J. A. Edge, J. Jones and M. A. Preece

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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I. P. Braidman, D. C. Anderson, C. J. P. Jones and J. B. Weiss

Bone cells released from perinatal rat calvaria by digestion with clostridial peptidase were separated into two distinct populations (designated types B and C) by equilibrium density centrifugation on a two-step gradient of Percoll. They were extensively characterized by light and electron microscopy and for behaviour in culture, acid and alkaline phosphatase activity, collagen synthesis, collagenase secretion and adenylate cyclase response to parathyroid hormone (PTH) and calcitonin. Type C cells were predominantly large with up to seven nuclei and an unusual cytoplasmic appearance in cytocentrifuge preparations. They did not proliferate in culture and we have established culture conditions which prevented their overgrowth by contaminating proliferative cells. In culture these cells had low alkaline and high acid phosphatase and high aryl sulphatase activity, and synthesized little collagen. In contrast type B cells were mostly smaller and many had irregular cytoplasmic projections. In culture they became polygonal in shape, proliferated rapidly, and reached confluence in 4–5 days. These were low in aryl sulphatase and acid phosphatase, high in alkaline phosphatase activity, and synthesized labelled collagen actively with [3H]proline and ascorbic acid included in the culture medium. The two cell populations were found to differ in culture in two important further respects. First, the type C cells showed an adenylate cyclase response to calcitonin but not to PTH, while the converse was true for type B cells; this was so over at least a 20-fold range of isobutylmethyl xanthine concentration. Secondly, type C cells in culture secreted an active collagenolytic enzyme. Type B cells secreted much lower levels of a predominantly latent collagenase which required activation by mersalyl. Co-culture of type C and type B cells led to a marked reduction in the content of active collagenase in the culture medium.

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P. ADAMS, T. M. CHALMERS, B. L. RIGGS JR. and J. D. JONES

SUMMARY

Calcium and phosphorus metabolism were studied in 22 patients with spontaneous primary hypothyroidism. Two patients were found to have hypercalcaemia but the mean serum calcium concentration of the group was significantly less than that of control subjects. The renal tubular reabsorption of phosphate was decreased and could be increased to normal with small calcium infusions. The response to calcium deprivation and to infusions of EDTA was abnormal and suggested an impaired ability to mobilize calcium from bone. There was a significant correlation between the defect in calcium mobilization, as judged from the response to EDTA, and the renal tubular reabsorption of phosphate.

In three patients serum parathyroid hormone concentrations, measured by radioimmunoassay, were in the upper part of the normal range.

It is suggested that in patients with hypothyroidism the target cells in bone are less responsive to the effects of parathyroid hormone than normal; as a consequence parathyroid hormone secretion may be increased.

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U. Beckford, J. Herbert, M. T. Jones, N. D. Martensz, S. A. Nicholson, B. Gillham and J. D. Hamer

ABSTRACT

Adrenocorticotrophin levels, measured by a cytochemical bioassay, were determined in the plasma and cerebrospinal fluid (CSF) of adult female rhesus monkeys which were ovariectomized and receiving oestrogen replacement therapy. In control monkeys, ACTH bioactivity was found in both CSF (10·2±1·8 ng/l) and plasma (186 ± 51 ng/l) in samples taken at 14.00 h (lights on: 07.00–19.00 h). Dexamethasone treatment (0·2 mg/kg) twice daily for 4 days suppressed plasma ACTH levels (52·8 ± 25·2 ng/l) but had no effect on CSF levels (7·6± 2·7 ng/l). Raising plasma ACTH, either by daily injections of a long-acting preparation of ACTH(1–24) for 6 days or by bilateral adrenalectomy (and subsequently withdrawing cortisol replacement therapy) also resulted in no detectable changes in ACTH levels in the CSF. A regression analysis between ACTH in the plasma and CSF from samples taken throughout the experiments showed no correlation. In contrast, measurement of ACTH by radioimmunoassay, whilst satisfactory for determination of this peptide in plasma, could not identify authentic ACTH in the CSF. It is concluded that bioactive ACTH does not enter the CSF in detectable quantities from either the peripheral vascular compartment or from the animal's own pituitary gland, and that reducing ACTH secretion from the pituitary also has no effect on levels of ACTH in the CSF. This is in marked contrast to other pituitary peptide hormones, including prolactin, which is secreted together with ACTH during 'stress' but which, unlike ACTH, enters the CSF relatively easily.

J. Endocr. (1985) 104, 331–338

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ML Krakowski, MR Kritzik, EM Jones, T Krahl, J Lee, M Arnush, D Gu, B Mroczkowski and N Sarvetnick

The upregulation of a limited number of growth factors in our interferon-gamma transgenic model for regeneration within the pancreas lead us to propose that these factors are important during pancreatic regeneration. In this study, we have assessed the influence of two growth factors within the pancreas, epidermal growth factor (EGF) and keratinocyte growth factor (KGF), by ectopically expressing these proteins under the control of the human insulin promoter in transgenic mice. This beta-cell-targeted expression of either EGF or KGF resulted in significant morphological changes, including cellular proliferation and disorganized islet growth. Intercrossing the individual Ins-EGF and Ins-KGF transgenic mice resulted in more profound changes in pancreatic morphology including proliferation of pancreatic cells and extensive intra-islet fibrosis. Insulin-producing beta-cells were found in some of the ducts of older Ins-EGF and Ins-EGFxKGF transgenic mice, and amylase-producing cells were observed within the islet structures of the double transgenic mice. These data suggest that both EGF and KGF are capable of affecting pancreatic differentiation and growth, and that co-expression of these molecules in islets has a more substantial impact on the pancreas than does expression of either growth factor alone.

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I. CHESTER JONES, D. K. O. CHAN, I. W. HENDERSON, W. MOSLEY, T. SANDOR, G. P. VINSON and B. WHITEHOUSE

Removal of the corpuscles of Stannius from the European eel (Anguilla anguilla L.) is followed by a fall in the concentration of plasma sodium and a rise in that of potassium and of calcium (Fontaine, 1964; Chester Jones, Henderson & Butler, 1965). It seemed possible that the corpuscles secrete corticosteroids, possibly aldosterone (Fontaine, 1963; Leloup-Hatey, 1964). A large quantity of corpuscles were therefore analysed for steroidogenetic capacity.

Fresh viscera from about 5000 eels, when gutted alive for commercial purposes, were obtained in Billingsgate Market. The corpuscles, a ventral pair on the posterior kidney, were removed in the Department of Zoology, St Bartholomew's Hospital Medical School, where the preliminary experiments were done.

Four experiments were carried out consisting of incubation of chopped corpuscles in a shaking incubator under air at 37° for 3 hr. The medium, isotonic with eel plasma, is given by Sandor et al. (1965). The substrate was a

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M. T. JONES, ELIZABETH M. TIPTAFT, F. R. BRUSH, D. A. N. FERGUSSON and R. L. B. NEAME

SUMMARY

The influence of several corticosteroids on stress-induced secretion of adrenocorticotrophin was studied. Two periods of inhibition were demonstrated. Fast feedback occurred within minutes with small doses of corticosterone, and was of short duration which was further curtailed as the dose of corticosterone was raised. Delayed feedback occurred after 1 h or later, required larger doses and the duration of inhibition was increased with increased dosage. Corticosterone and cortisol were agonists on both fast and delayed feedback. However, 11-deoxycorticosterone and 11-deoxycortisol were antagonists on fast feedback but agonists on delayed feedback. It is concluded that the two feedback mechanisms have different dynamics and separate receptors.