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Nuffield Institute for Medical Research, University of Oxford, Headley Way, Oxford, 0X3 9DS
(Received 20 February 1976)
During the latter third of gestation undisturbed foetal sheep with chronically implanted vascular catheters have higher plasma adrenocorticotrophin (ACTH) concentrations than adult sheep (Boddy, Jones, Mantell, Ratcliffe & Robinson, 1974; Jones, Boddy, Robinson & Ratcliffe, 1975a). This is probably the result of a higher rate of secretion from the foetal pituitary (Jones, Luther, Ritchie & Worthington, 1975 b). The plasma glucose concentration of foetal sheep is substantially lower than that of mature sheep (Shelley, 1973). Since hypoglycaemia is a potent stimulus for ACTH secretion (Yalow, Varsano-Aharon, Echemendia & Berson, 1969; Vague, Oliver & Vague, 1972) a correlation between the plasma glucose and ACTH concentrations in pregnant and foetal sheep has been sought.
Plasma samples were collected from 60 pregnant and foetal sheep with chronically implanted carotid arterial catheters as previously described (Boddy et al.
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SUMMARY
Although dehydroepiandrosterone sulphate has been recognized as one of the major secretory products of the human adrenal gland neither its biosynthetic pathway nor its site of formation within the cortex have been extensively studied. Ultramicrochemical techniques, which relate enzymic activity to well-defined groups of cells, have been used in the work now described to study the sulphation of dehydroepiandrosterone in the zones of the guinea-pig adrenal cortex. It has been shown that dehydroepiandrosterone sulphokinase activity resides only in the compact cell of the zona reticularis.
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ABSTRACT
The regulatory factors controlling uterine activity during pregnancy remain unclear in many species. Since myometrial relaxants raise intracellular cyclic AMP, modulation of signalling pathways coupling cell-surface receptors to adenylate cyclase activation could be an important site for control. To assess the functional activity of the stimulatory GTP-binding protein Gs we have measured adenylate cyclase activation by GTP, its non-hydrolysable analogue guanosine 5′-(β-γ-imido)triphosphate (Gpp(NH)p), fluoride, forskolin and manganese in a 50 000 g membrane fraction prepared from the myometrium of non-pregnant, mid-pregnant (30–32 days) and late-pregnant (62–66 days) guinea-pigs (full term 67±2 days). While forskolin- and manganese-dependent enzyme activation was unaltered by pregnancy, maximal stimulation by Gpp(NH)p and fluoride was enhanced by up to 200%. Recovery of adenylate cyclase activity in the 50 000 g fraction was essentially constant at 20–24% of the total activity throughout pregnancy, and thus cannot explain the increases observed. Since guanine nucleotides and fluoride stimulate adenylate cyclase through activating Gs, and forskolin and manganese act at the level of the catalytic unit, these data are consistent with a pregnancy-related increase in Gs functional coupling while adenylate cyclase activity is unaltered. These observations suggest a physiological regulation of myometrial Gs activity during pregnancy which could facilitate hormonal stimulation of adenylate cyclase and contribute to uterine quiescence by increasing uterine sensitivity to relaxants.
Journal of Endocrinology (1990) 127, 15–21
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INTRODUCTION
Cytokines are soluble polypeptides released from cells of the immune system. Their production in endocrine glands and their actions on hormone-responsive cells is currently a subject of intense research interest. There is strong evidence for the involvement of cytokines in the pathogenesis of autoimmune diabetes and thyroid disease. In addition they may regulate the growth and differentiated function of cells as they are known to do in the reticuloendothelial system. Cytokines may thus contribute to the development of functional endocrine disturbances and neoplasms. They are also involved in bone modelling processes and their action may be disturbed in disorders of bone. Greater understanding of the effects of cytokines will give insight into normal regulatory processes in endocrine tissues and may lead to therapeutic advances. The aim of this article is to review these actions and to speculate as to their physiological and pathophysiological significance as well as
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Nuffield Institute for Medical Research, University of Oxford, Oxford, 0X3 9DS
(Received 11 March 1976)
Vasopressin is considered an important hormone controlling adrenocorticotrophin (ACTH) secretion under some conditions (De Wied, Bohus, Ernst, de Jong, Nieuwenhuizen, Pieper & Yasumura, 1968). Its infusion into dogs at pharmacological but not physiological doses increases plasma ACTH concentration (Andersen & Egdahl, 1964). It behaves as a corticotrophin-releasing factor on incubation with anterior pituitary cells (Portanova, Smith & Sayers, 1970). Moreover a neuroendocrine vasopressin pathway possibly associated with ACTH secretion has been proposed (Parry & Livett, 1973). During hypoxaemia in the foetal sheep there is a rise in both plasma ACTH and vasopressin (Alexander, Britton, Forsling, Nixon & Ratcliffe, 1973; Boddy, Jones, Mantell, Ratcliffe & Robinson, 1974b; Rurak, 1976). Thus the possibility that a rise in foetal plasma vasopressin is responsible for the increased secretion of ACTH during hypoxaemia has been investigated. Foetal and maternal vascular
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SUMMARY
The rat hypothalamus in vitro preparation was used to investigate the effect of bilateral adrenalectomy, with and without replacement therapy, on the release of corticotrophin-releasing factor (CRF). Corticotrophin-releasing factor was estimated using 48 h basal hypothalamic lesioned assay rats and corticosterone production of excised adrenals was used as the end point.
Bilateral adrenalectomy resulted in depletion of hypothalamic CRF content within the first 2 h after the operation but this effect was prevented by replacement therapy with corticosterone. Thereafter, the hypothalamic CRF content returned to values not significantly different from the intact control level. Bilateral adrenalectomy caused an increase in both basal and acetylcholine-induced release of CRF and it is suggested that corticosteroids exert a negative feedback effect on the hypothalamus.
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Department of Human Metabolism, Robert Hague Centre for Diabetes and Endocrinology, Medical School, The University of Sheffield, Sheffield S10 2RX, UK
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Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms.
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Department of Human Metabolism, Robert Hague Centre for Diabetes and Endocrinology, Medical School, The University of Sheffield, Sheffield S10 2RX, UK
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Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.
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In earlier studies (Bridges & Jones, 1967, 1968) we found a significant relationship between adrenocortical responses to the psychological stress of an oral university examination (2nd M.B. Anatomy examination) and body-build, assessed by means of phenotyping by the method of Parnell (1958). This assumes three basic components of physique: fatness (F), muscularity (M) and linearity (L). It was found that the mean plasma corticosteroid concentration at the time of the examination was significantly greater in the primarily linear group than in the mainly muscular students, and there was a significant negative correlation between the examination corticosteroid values and the muscularity scores (r = − 0·225; P < 0·05). One explanation for these findings would be that the muscular group was characterized by a lower sensitivity of adrenocortical response. It was decided to test this possibility using the methods of Landon, James, Wharton & Friedman (1967).
For the present study, 38 students
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SUMMARY
A method is described for the preparation of isotopically pure [3H]oxytocin and [3H]vasopressin from the pooled posterior pituitary glands of groups of four or five rats after the intracisternal injection of [3H]tyrosine. Hormones were separated from deproteinized neurohypophysial extracts by chromatography on Amberlite CG-50, and further purified by chromatography on carboxymethylcellulose. In this way, samples of the hormones were obtained with a very high degree of isotopic purity. The method is suitable for studying the effects of stimuli to the hypothalamo—neurohypophysial system on the biosynthesis and transport of the hormones.
