Endocrine programming and fetal origins of adult disease David I.W. Phillips Trends in Endocrinology and Metabolism 2002, 13:363   During the past decade, a substantial body of evidence has emerged showing that low birthweight or other indices of reduced fetal growth are associated with a raised prevalence of cardiovascular disease (CVD) in adult life and its antecedents, including raised blood pressure, glucose intolerance and dyslipidaemia. These comprise the metabolic or insulin-resistance syndrome [1]. This evidence originated in studies carried out by David Barker and his colleagues (described here by Barker), but the findings have now been extensively replicated in studies elsewhere. New findings described in his review suggest that these effects of early growth retardation are particularly evident in humans who show compensatory or 'catch-up' growth and later develop obesity. These studies have led to the hypothesis that these common adult diseases might originate during fetal development. It is suggested that environmental factors affect the developing fetus, permanently altering its morphology and physiology, and predisposing it to the metabolic syndrome and CVD. This hypothesis is strongly supported by animal experiments, which show that adverse influences, such as undernutrition during gestation, result in the birth of offspring with a variety of morphological and physiological changes that, when combined with an obesity-inducing diet, leads to diabetes and the metabolic syndrome (see review by Ozanne and Hales). These intriguing findings raise the question as to the nature of the underlying processes that link early growth restriction with these long-term health consequences. There is growing evidence that an adverse early environment influences cellular proliferation and the differentiation of several organ systems. For example, maternal protein restriction in animal models is associated with reductions in pancreatic -cell mass [2], diminution in nephron number (see review by Dodic et al.) and alterations in the zonation of the liver, with an increased capacity for gluconeogenesis [3]. Studies of humans show that low birthweight is associated with adverse changes in body composition, with increased adipose but reduced muscle mass [4,5] . However, it is becoming clear that an important way in which the early environment can have long-term effects is by resetting key hormonal systems that control growth and development. It is well established that these systems can be 'programmed' during development. For example, over 50 years ago it was shown that the early differentiation of the hypophysis into male or female depends on whether a testis is present. Low concentrations of androgens in the perinatal period imprint the hypothalamus so that gonadotrophins are secreted in the female, cyclical pattern, whereas high concentrations of androgens lead to the tonic secretion of gonadotrophins, which is the male pattern [6]. Manipulation of androgen or estrogen concentrations soon after birth leads to changes in sexual behaviour. In females, it also leads to the development of sterile anovulation and polycystic ovaries. The central theme of this special issue of TEM is that the early experience of an individual affects the development of a diverse range of hormonal systems, which, in turn, might influence the predisposition to adult CVD and metabolic disease. It is suggested that the biological 'purpose' of these mechanisms is to adapt the organism to its environment. If a pregnant animal is exposed to an unfavourable environment, such as undernutrition, it is logical that the development of the offspring should be adapted for that environment. If, however, these offspring are relatively overnourished, the prenatal programming might be inappropriate and lead to disease. This is an attractive model that might well account for many of the reported epidemiological findings. There is compelling evidence from animal studies that the hypothalamic–pituitary–adrenal (HPA) axis is highly susceptible to programming during development, and recent studies of humans have reported subtle alterations in the HPA in association with low birthweight. Matthews reviews this rapidly developing field and the possibility that the adrenocortical response to stress might be altered by the early environment. The sympathetic nervous system is known to be highly plastic and susceptible to the influence of environmental factors during development. One of these factors is environmental temperature, and Young reviews the human and animal evidence that thermoregulatory mechanisms involving the sympathetic nervous system might be programmed during fetal life. The theme of programming of reproductive function is discussed by Davies and Norman. In the search for mechanisms that could link the early environment with adult disease, the growth hormone–insulin growth factor-I axis has been proposed as a candidate. As Holt describes in his review, this system is known to be nutritionally regulated in the fetus and abnormalities are reported in growth-retarded fetuses and neonates. Finally, the reviews by Kennaway and Dodic et al. are an important reminder that several vegetative hypothalamic functions, such as circadian rhythmicity and the regulation of fluid balance and appetite [7], are also vulnerable to maternal influences. Much of the work described in these reviews is groundbreaking and clearly much remains to be done. However, the concept of hormonal programming is now well established, and has become a new frontier in endocrine research, which could have important implications for public health.   Go to the Full Article > >  As a BioMedNet member you have free full-text access to this article within BioMedNet Reviews for 14 days  You will have full-text access to all articles if your institute subscribes. Recommend a subscription to your librarian  There are 15,000 more Review articles in BioMedNet Reviews  Please send us your feedback on this magazine		BioMedNet Magazine 9th - 22nd October 2002 Magazine Home Email to a Friend Full Article PDF printer ready version   Further Reading* Programming and reproductive functioning [Review] Michael J. Davies and Robert J. Norman Trends in Endocrinology and Metabolism 2002, 13:386-392   Fetal programming of coronary heart disease [Review] David J.P. Barker Trends in Endocrinology and Metabolism 2002, 13:364-368   Early programming of the hypothalamo–pituitary–adrenal axis [Review] Stephen G. Matthews Trends in Endocrinology and Metabolism 2002, 13:373-380   Early programming of glucose–insulin metabolism [Review] Susan E. Ozanne and C. Nicholas Hales Trends in Endocrinology and Metabolism 2002, 13:368-373   Fetal programming of the growth hormone–insulin-like growth factor axis [Review] Richard I.G. Holt Trends in Endocrinology and Metabolism 2002, 13:392-397     * Full text access to the journal articles above is available to BioMedNet Reviews institutional subscribers     Profile: David Barker [Conference report] Pete Moore The American Society of Human Genetics October 4-7 2000 Fetal stress can last a lifetime [Conference report] Pete Moore The American Society of Human Genetics October 4-7 2000   Related Links in BioMedNet Reviews Journal Table of Contents Table of Contents by email Related Full Text Articles Browse Evolution Browse Endocrinology Browse Molecular Medicine Browse Physiology Search BioMedNet Reviews