David I.W. Phillips, University of Southampton, Southampton SO16 6YD, UK

There is a now a large body of data linking an adverse early environment as indicated by small size at birth with a higher prevalence of cardiovascular and metabolic disease in adult life [1]. However, it is still unclear as to how events in utero can affect disease predisposition some five to six decades later. Recently there has been much interest in the possibility that the early environment may have long-term effects through resetting of a diverse array of hormonal systems that control growth and development. (For review see [2]) It has been known for a long time that the set-point of these systems is plastic and can be programmed or permanently altered by events in utero or early infancy. Several neuroendocrine systems appear to be involved but of particular importance is evidence that the major hormonal systems which mediate the stress response (including the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system) are involved. Because the hormonal mediators of the stress response including glucocorticoids and catecholamines have biologically potent effects on metabolism and the vasculature, it has proved to be an attractive idea that these may have an important role in mediating the effects of the early environment.

A number of studies now suggest that people of low birth weight do have an enhanced biological response to stress. The first observation came from studies of a large cohort of Swedish army recruits which showed a continuous relationship between size at birth and stress susceptibility at a psychological assessment which was carried out to assess their suitability for military combat duties [3]. These results are supported by a German study of young healthy males who were exposed to the Trier Social Stress Test: a psychological stress test involving a public speaking task. Cortisol responses to the stress exposure were significantly and inversely related to the subjects' birth weight [4]. In a recent study, we demonstrated that low birth weight is associated with enhanced blood pressure and heart rate responses to psychological stressors in women but not men [5]. Further analyses of the data were carried out using spectral analysis techniques and autoregressive estimation of baroreflex function (a primary controller of blood pressure). This suggested that birth weight was associated with modulation of both sympathetic and parasympathetic function. It also provided the first human evidence of a relationship between size at birth and altered baroreflex function [6]. Given emerging evidence that blood pressure reactivity to psychological stressors predicts later hypertension, this provides a potential explanation, in women, for previously described associations between reduced fetal growth and raised blood pressure in later life. The findings of these studies suggested that there were marked gender differences in the nature of the relationship between size at birth and the stress response. We have recently carried out a study of young children born in Southampton, who formed part of a prospective study of mothers and babies born in a local maternity hospital. The psychological test used was the Trier Social Stress Test adapted for children which has been shown to give good adrenocortical responses. In this test, children are asked to perform a public speaking task involving storytelling and mental arithmetic for a panel of three unknown adult “judges.” We measured changes in salivary cortisol secretion and assessed autonomic function with a BIOPAC which records pulse and blood pressure changes, the ECG, and cardiac impedance from which a variety of indices of autonomic function can be obtained. In a cross-sectional study of 68 boys and 72 girls (aged 7-9 years) there were again marked gender differences. In boys, markers of fetal growth restriction, such as low birth weight, were associated with raised arterial pressure and systemic vascular resistance, particularly following the stress test. In contrast, girls who were small at birth showed no such associations, but did show greater cardiac sympathetic nervous system activation as indicated by measures of pre-ejection period and corrected QT interval, both at rest and during stress. Salivary cortisol responses were related to birth weight, head circumference, and ponderal index at birth in boys, but again not in girls [7]. These findings appeared to be independent of possible confounding factors such as obesity, education or social class.

The HPA Axis and the Adult Metabolic or Vascular Disease

Per Bjorntorp was among the first to suggest that a neuroendocrine disturbance involving the HPA axis may play an important part in the causation of the metabolic syndrome [8], As patients with Cushing’s syndrome develop a severe form of the metabolic syndrome with hypertension, insulin resistance, glucose intolerance, dyslipidemia, and central obesity, it is an attractive idea that less profound disturbances of the HPA might underlie the metabolic syndrome. Case-control and cross-sectional studies of people without pituitary or adrenal disease show that elevated plasma cortisol concentrations in morning samples are associated with high blood pressure, glucose intolerance, insulin resistance, and hyperlipidaemia [9]. However an increasing body of evidence also suggests that physiological alterations in autonomic responses are also likely to be involved in the syndrome and the related risk of cardiovascular disease. For example, stress responsiveness to stressors which predominantly involve sympathetic activation are associated with carotid atherosclerosis [10], increased left ventricular mass [11,12] and in follow-up studies, with subsequent blood pressure [13] and the prevalence of hypertension [14].

The HPA Axis, “Life History,” and the Development of Adult Disease

It is also possible that the HPA axis and related neuroendocrine responses may be acting in a different and more subtle way to determine the risk of adult disease. This insight into a possible alternative role of the HPA axis has emerged from the development of “life-history” theory in biology. Life history theory describes the way in which organisms prioritize critical events or processes. These include the age at first reproduction, the effort expended in reproducing (for example litter size and the number of reproductive events), length of life, and the onset of senescence. These choices are made during development and usually involve “trade-offs” such that the eventual phenotype is optimally adapted for the environment. Usually the process involves resource allocation between three competing priorities, growth, reproduction, and maintenance. Allocation of resources to one area, for example increased reproduction will reduce the resources available for other processes such as longevity. A vivid example of this was a study of the British Monarchy which provided evidence that female longevity was negatively correlated with the number of progeny and positively correlated with age at first childbirth [15]. Every species appears to be distinctive in the way in which these trade-offs are carried out, but neuroendocrine processes appear to play a central role in most instances.
Given its widespread occurrence in biology, it would be surprising if human development did not involve the generation of alternative phenotypes in response to the environment in which individuals developed. It is also likely that variation in life history involves neuroendocrine mechanisms and in particular the HPA axis. This requires a change in the way we understand the function of these neuroendocrine systems [16]. Hitherto, the HPA axis and sympathoadrenal system have been viewed in terms of their function as mediators of the classical stress response. However, the HPA axis may well have an important role in directing resource partitioning during development among competing demands leading to the development of different phenotypes according to the prevailing environmental conditions. Glucocorticoids regulate food intake and body weight and have a wide range of effects in multiple systems involved in growth, maintenance, and reproductive strategy. Most information on the biology of the HPA axis derives from clinical studies using pharmacological quantities of glucocorticoids. As yet we know relatively little as to how subtle changes in the HPA axis or the related sympathoadrenal system might impact on the development of the phenotype. We also know little as to how this might be advantageous in adverse circumstances or lead to adult pathology in conditions of nutritional excess. How fetal programming of neuroendocrine systems occurs, the mechanisms involved, and the effects on health have been largely neglected by endocrinologists. Yet this area has much promise in explaining some of the differences in the health and well-being of populations who have had different early experiences either within one or several generations. The underlying science is clearly complex but may lead to new ways of understanding both the underlying processes and intervening in the development of the major diseases which are now among the most common causes of ill-health in both the developed and developing world.

References

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8. Björntorp P. Visceral Obesity: A "civilization syndrome". Obesity Res 1993;1:206-22.
9. Phillips DIW, Barker DJP, Fall CHD, et al. Elevated plasma cortisol concentrations: A link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 1998;83:757-60.
10. Everson SA, Lynch JW, Chesney MA, et al. Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study. Brit Med J 1997;314:553-58.
11. Kamark TW, Eranen J, Jennings JR, et al. Anticipatory blood pressure responses to exercise are associated with left ventricular mass in Finnish men: Kuopio Ischemic Heart Disease Risk Factor Study. Circulation 2000;102:1394-99.
12. Allen MT, Matthews KA, Sherman FS. Cardiovascular reactivity to stress and left ventricular mass in youth. Hypertension 1997;30:782-87.
13. Treiber FA, Turner JR, Davis H, Thompson W, Levy M, Strong WB. Young children's cardiovascular stress responses predict resting cardiovascular functioning 2 1/2 years later. J Cardiovascular Risk 1996;3:95-100.
14. Menkes MS, Matthews KA, Krantz DS, et al. Cardiovascular reactivity to the cold pressor test as a predictor of hypertension. Hypertension 1989;14:524-30.
15. Westendorp RG, Kirkwood TB. Human longevity at the cost of reproductive success. Nature 1998;396(6713):743-46.
16. Worthman CM, Kuzara J. Life history and the early origins of health differentials. Am J Hum Biol 2005;17(1):95-112.

 

Please address correspondence to:
D.I.W. Phillips
MRC Resource centre
Southampton General Hospital
Tremona Road
Southampton SO16 6YD, UK
Tel: +44 23 8077 7624
Fax: +44 23 8070 4021
Email: diwp[at]mrc.soton.ac.uk