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H. M. Docherty, M. J. Dixon-Lewis, P. G. Milton, A. Blight and D. A. Heath

ABSTRACT

The distribution and molecular characteristics of parathyroid hormone-related protein (PTH-rP) in conditioned media and cell extracts of cultured human keratinocytes, and in media from a variety of both normal and transformed epithelial and non-epithelial cell cultures were studied. PTH-rP of M r 20 000 was observed in keratinocyte-conditioned media, and a larger form, M r 29 000, in the keratinocyte cell extract. PTH-like bioactivity was also detected in media from 12 out of 17 epithelial cell cultures, but was not present in media from 14 cell cultures of non-epithelial origin. The molecular size of the PTH-like protein present in the epithelial cell media was approximately 20 000, corresponding with the PTH-rP in keratinocyte-conditioned medium. These observations may explain why hypercalcaemia is most commonly associated with tumours of epithelial origin.

Journal of Endocrinology (1989) 123, 487–493

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N. DESHPANDE, VIBEKE JENSEN, PAMELA CARSON, R. D. BULBROOK and A. A. LEWIS

SUMMARY

The production rate of cortisol based on both the plasma clearance of the hormone (plasma production rate) and the urinary metabolite method (urinary production rate) was simultaneously measured in early or advanced breast cancer patients and in controls. Higher production of the hormone was observed by both these methods in patients with advanced breast cancer.

There was a significant correlation between the plasma production rate of cortisol and its urinary production based on the specific activities of three urinary metabolites, namely, cortisol, tetrahydrocortisol (THF) and tetrahydrocortisone (THE). However, the values obtained for the urinary production rate differed considerably in about one-third of the patients due to differences in the specific activities of THE and THF. It is postulated that, in some cases, there may be a second precursor of urinary THE and THF which contributes significant amounts to the excretion of these metabolites.

No correlation was found between the cortisol production rate and urinary total 17-hydroxycorticosteroids (17-OHCS).

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B. A. LARSON, T. L. WILLIAMS, M. O. SHOWERS and U. J. LEWIS

Naturally occurring diabetogenic substance (NDS), isolated from clinical grade human growth hormone (hGH), induces insulin release from isolated pancreatic islets of hypo-physectomized rats in the presence of Krebs–Ringer bicarbonate solution (KRB) containing 2·8 mmol glucose/l. To determine the role of extracellular glucose in insulin release mediated by NDS, islets were perifused with glucose-free KRB containing 200 μg NDS/ml. Under these conditions NDS induced prompt insulin release (284 ± 34 (s.e.m.)% over basal insulin secretion) (P < 0·0005). Islets perifused with 16·7 mmol glucose/l before and during exposure to 200 μg NDS/ml released additional insulin with exposure to NDS (199 ± 28% over basal insulin secretion) (P< 0·0005). Purified intact hGH (200 μg/ml) did not induce insulin release in the presence of 16·7 mmol glucose/l. Mannoheptulose (5 mmol/l) did not inhibit insulin release mediated by NDS but did inhibit insulin release stimulated by 16·7 mmol glucose/l (P< 0·0005). Islets were pre-incubated for 90 min with 200 μg NDS/ml or 200 μg intact hGH/ml KRB and 2·8 mmol glucose/l to determine what effect either protein might have on subsequent glucose-stimulated (16·7 mmol/l) insulin release. Islets pre-incubated with NDS responded with no less insulin release than islets pre-incubated with intact hGH. Naturally occurring diabetogenic substance initiated insulin release in the absence of extracellular glucose, stimulated additional secretion in the presence of stimulatory glucose concentrations and did not inhibit subsequent islet response to glucose. Naturally occurring diabetogenic substance did not depend on glucose phosphorylation to initiate insulin release.

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C. E. Lewis, A. Megson, J. F. Morris and H. M. Charlton

ABSTRACT

We have investigated the effects of multiple 2-hourly injections of LH-releasing hormone (LHRH) on the number and size of the gonadotrophs and gonadotroph secretory granules, and the lipid content of gonadotrophs in the pituitary glands of intact and gonadectomized male and female hypogonadal (hpg) mice. Gonadotrophs were identified by immunocytochemistry for LHβ, and the size and secretory status of the gonadotrophs were assessed by quantitative ultrastructural analysis of immunoidentified gonadotrophs. The administration of 60 ng LHRH by subcutaneous injection every 2 h for 15 days resulted in an increase in the number, size and granule content of LHβ-immunoidentified gonadotrophs of hpg mice to values found in normal adult mice. Large lipid droplets accumulated in 30–40% of the gonadotrophs in both male and female LHRH-treated hpg mice. Although lipid-containing gonadotrophs were larger than lipid-free cells in all LHRH-treated groups irrespective of the presence or absence of gonads, a marked difference in the number, position within the cell, and size of the secretory granules between the lipid-containing and lipid-free cells was found only in the pituitary glands of intact LHRH-treated hpg females.

These results demonstrate: (a) that the effects of multiple injections of LHRH on the morphology of the gonadotrophs of hpg mice is not dependent on the presence of functioning gonads, although ovarian factors are required for the full development of morphological, and hence possibly functional, heterogeneity in the gonadotroph population in female animals, and (b) that, although multiple injections of LHRH in hpg mice are more effective than single daily injections of LHRH in stimulating pituitary-gonadal function, there is no obvious difference in the morphologically recognizable effects that these two modes of administration have on the pituitary gonadotrophs.

J. Endocr. (1986) 111, 483–493

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NJ Lewis-Barned, WH Sutherland, RJ Walker, SA de Jong, HL Walker, EA Edwards, V Markham and A Goulding

This study was designed to determine the effect of menopause and hormone replacement therapy (HRT) on plasma cholesteryl ester fatty acid (CEFA) composition and insulin sensitivity and the relationships between these variables in perimenopausal women (aged 40-55 years) including 49 who were premenopausal and 32 who were postmenopausal. Plasma cholesteryl ester proportions of dihomo-gamma-linolenic acid (20:3 n-6) were correlated significantly with insulin sensitivity index (r=-0.319, P=0.005), fasting serum insulin levels (r=0.230, P=0.038), body mass index (r=0.242, P=0.03) and per cent body fat (r=0.329, P=0.003) in perimenopausal women (n=81). Similar associations were observed in premenopausal women. Regression analysis suggested the relationships between 20:3 n-6 proportions and indices of insulin action may be partly mediated by levels of adiposity. In postmenopausal women, 6 months of HRT significantly (P=0.008) increased the ratio of arachidonic acid (20:4 n-6) to linoleic acid (18:2 n-6), which is an indicator of activity in the pathway of 20:4 n-6 synthesis, compared with placebo. These findings suggest that the type of fat in the diet indicated by plasma CEFA composition is linked to adiposity and insulin action. They also suggest that in postmenopausal women, HRT may increase the synthesis of 20:4 n-6, which is the precursor for eicosanoids with important cardiovascular functions.

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M. Caleffi, I. S. Fentiman, G. M. Clark, D. Y. Wang, J. Needham, K. Clark, A. La Ville and B. Lewis

ABSTRACT

As part of a controlled trial of the use of tamoxifen for the treatment of mastalgia, some of the metabolic and haematological effects of this agent were measured. A panel of haemostatic variables including prothrombin time, kaolin cephalin clotting time, fibrinogen, euglobulin lysis time, factor VII, factor VIII, protein C and anti-thrombin III were determined. In addition, levels of sex hormone-binding globulin and both total and free oestradiol were estimated. No alteration in clotting function was found during the administration of tamoxifen, although hepatic function did alter during this period with an increase in concentration of sex hormone-binding globulin. There was a significant increase in total oestradiol and free oestradiol although the percentage of biologically available free oestradiol fell slightly during the course of tamoxifen treatment. There was a slight reduction in low-density lipoprotein cholesterol with an increase in HDL2, a subclass of high-density lipoprotein (HDL) cholesterol, consistent with an oestrogen-agonist effect. These data suggest that tamoxifen administration does not adversely influence haemostatic mechanisms or lipoprotein metabolism in the short term.

J. Endocr. (1988) 119, 335–339

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F. R. BELL, D. E. WEBBER, J. A. H. WASS, LESLEY H. REES, JOAN EVANS, LINDA M. MARGAN, V. MARKS and JANE LEWIS

Levels of endogenous somatostatin, gastric inhibitory polypeptide (GIP), glucagon and insulin were measured during gastric (abomasal) emptying in the conscious calf. Isotonic NaHCO3 infused into the duodenum increased rates of emptying of a saline test meal and of gastric acid secretion, but had no effect on basal levels of blood glucose, somatostatin, GIP, insulin or glucagon. By contrast, intraduodenal infusion of 60 mm-HCl caused complete inhibition of gastric emptying, reduction of acid secretion, and an immediate increase in plasma somatostatin from 121·3 ± 9·4 (s.e.m.) to 286·3 ± 16·3 pg/ml (P <0·01) but levels of GIP, insulin, glucagon and glucose were unaltered. Intravenous injection of somatostatin (0·5 μg/kg) suppressed the antral electromyographic recording and gastric efflux so long as plasma somatostatin levels remained above approx. 200 pg/ml. This suggests that somatostatin can be released by intraduodenal acidification and that it inhibits gastric function by an endocrine effect. Since somatostatin retards gastric emptying it may therefore have an indirect role in nutrient homeostasis by limiting discharge of gastric chyme to the duodenum.

Open access

Lesley A Hill, Dimitra A Vassiliadi, Ioanna Dimopoulou, Anna J Anderson, Luke D Boyle, Alixe H M Kilgour, Roland H Stimson, Yoan Machado, Christopher M Overall, Brian R Walker, John G Lewis and Geoffrey L Hammond

Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies.