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      Long-Term Consequences of Intrauterine Growth Retardation

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          Abstract

          Recent studies in Europe, North America and the developing world have shown that low birth weight or other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of raised blood pressure, non-insulin-dependent diabetes and cardiovascular disease in late adult life. These findings have led to the ‘fetal origins’ hypothesis which proposes that fetal adaptations to an adverse intrauterine environment programme persistent physiological and metabolic changes which predispose to these diseases. The mechanisms are unknown, but evidence from animal studies and preliminary evidence in humans suggest that impaired fetal nutrient supply permanently alters neuroendocrine development in the offspring resulting in long-term changes in the set point of adrenocortical and sympathoadrenal hormonal activity.

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          Cellular mechanisms underlying the development and expression of individual differences in the hypothalamic-pituitary-adrenal stress response.

          Several years ago Levine, Denenberg, Ader, and others described the effects of postnatal "handling" on the development of behavioral and endocrine responses to stress. As adults, handled rats exhibited attenuated fearfulness in novel environments and a less pronounced increase in the secretion of the adrenal glucocorticoids in response to a variety of stressors. These findings clearly demonstrated that the development of rudimentary, adaptive responses to stress could be modified by environmental events. We have followed these earlier studies, convinced that this paradigm provides a marvellous opportunity to examine how subtle variations in the early environment alter the development of specific neurochemical systems, leading to stable individual differences in biological responses to stimuli that threaten homeostasis. In this work we have shown how early handling influences the development of certain brain regions that regulate glucocorticoid negative-feedback inhibition over hypothalamic-pituitary-adrenal (HPA) activity. Specifically, handling increases glucocorticoid (type II corticosteroid) receptor density in the hippocampus and frontal cortex, enhancing the sensitivity of these structures to the negative-feedback effects of elevated circulating glucocorticoids, and increasing the efficacy of neural inhibition over ACTH secretion. These effects are reflected in the differential secretory pattern of ACTH and corticosterone in handled and nonhandled animals under conditions of stress. In more recent years, using a hippocampal cell culture system, we have provided evidence for the importance of serotonin-induced changes in cAMP levels in mediating the effect of postnatal handling on hippocampal glucocorticoid receptor density. The results of these studies are consistent with the idea that environmental events in early life can permanently alter glucocorticoid receptor gene expression in the hippocampus, providing evidence for a neural mechanism for the development of individual differences in HPA function.
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            Association between low birthweight and high resting pulse in adult life: is the sympathetic nervous system involved in programming the insulin resistance syndrome?

            To test the hypothesis that elevated sympathetic nervous system (SNS) activity could be determined in utero and be one of the processes mediating the link between size at birth and insulin resistance and raised blood pressure in adult life, we have studied the resting pulse rate of 449 men and women aged 46 to 54 (mean 50) years born in Preston, Lancashire, England whose birth size was recorded in detail. The subjects were visited at home by trained fieldworkers who measured resting pulse rate and blood pressure using an automated recorder. The resting pulse rate ranged from 44 to 108 (mean 73) beats min(-1). It rose with increasing body mass index (r = 0.14, p = 0.003) and waist to hip ratio (adjusted for sex r = 0.10, p = 0.003) and correlated significantly with systolic and diastolic blood pressures (p = 0.001), fasting glucose (p = 0.02), split proinsulin (p = 0.001), and triglyceride concentrations (p = 0.02). The pulse rate fell progressively from 76 beats min(-1) among subjects who weighed 5.5 lb (2.5 kg) or less at birth to 71 beats min(-1) among those who weighed 7.5 lb (3.3 kg) or more (decline in pulse rate per kg increase in birthweight = 2.7, 95 % CI 0.6 to 4.8 beats min(-1). The association was independent of current body mass index, waist to hip ratio and of potential confounding variables including smoking, alcohol consumption, and social class. Although the resting pulse rate is an imperfect index of SNS activity, these findings are consistent with the hypothesis that elevated SNS activity established in utero is one mechanism linking small size at birth with the insulin resistance syndrome in adult life.
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              Intrauterine programming of hypertension by glucocorticoids

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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                978-3-8055-6700-8
                978-3-318-00313-0
                1663-2818
                1663-2826
                1998
                April 1998
                17 November 2004
                : 49
                : Suppl 2
                : 28-31
                Affiliations
                Metabolic Programming Group,Medical Research Council (University of Southampton), Southampton General Hospital, Southampton, UK
                Article
                53084 Horm Res 1998;49(suppl 2):28–31
                10.1159/000053084
                9730669
                f9395a42-5d7a-4071-83c2-2cdebe11e575
                © 1998 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 1, Tables: 2, References: 28, Pages: 4
                Categories
                Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Cardiovascular disease,Programming,Hypertension,Fetal growth,Birth weight,Type-2 (non-insulin-dependent) diabetes

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