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Elevated Plasma Cortisol Concentrations: A Link between Low Birth Weight and the Insulin Resistance Syndrome?¹

Medical Research Council Environmental Epidemiology Unit, University of Southampton (D.I.W.P., D.J.P.B., C.H.D.F, C.B.W.), and the Regional Endocrine Unit, Southampton General Hospital (P.W.), Southampton, United Kingdom; and the Department of Medicine, University of Edinburgh, Western General Hospital (J.R.S., B.R.W.), Edinburgh, Scotland

Address all correspondence and requests for reprints to: Dr. D. I. W. Phillips, Medical Research Council Unit, Southampton General Hospital, Tremona Road, Southampton, United Kingdom SO16 6YD. E-mail: diwp{at}mrc.soton.ac.uk

	Abstract

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Recent studies have shown that reduced fetal growth is associated with the development of the insulin resistance syndrome in adult life. The mechanisms are not known. However increased activity of the hypothalamic-pituitary-adrenal axis (HPAA) may underlie this association; the axis is known to be reset by fetal growth retardation in animals, and there is evidence in humans of an association between raised HPAA activity and the insulin resistance syndrome. We have, therefore, examined the relations among size at birth, plasma cortisol concentrations, and components of the insulin resistance syndrome in a sample of healthy men. We measured 0900 h fasting plasma cortisol and corticosteroid-binding globulin levels in 370 men who were born in Hertfordshire, UK, between 1920–1930 and whose birth weights were recorded. Fasting plasma cortisol concentrations varied from 112–702 nmol/L and were related to systolic blood pressure (P = 0.02), fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test (P = 0.0002 and P = 0.04), plasma triglyceride levels (P = 0.009), and insulin resistance (P = 0.006). Plasma cortisol concentrations fell progressively (P = 0.007) from 408 nmol/L in men whose birth weights were 5.5 lb (2.50 kg) or less to 309 nmol/L among those who weighed 9.5 lb (4.31 kg) or more at birth, a trend independent of age and body mass index. These findings suggest that plasma concentrations of cortisol within the normal range could have an important effect on blood pressure and glucose tolerance. Moreover, this study provides the first evidence that intrauterine programming of the HPAA may be a mechanism underlying the association between low birth weight and the insulin resistance syndrome in adult life.

	Introduction

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STUDIES in both Europe and North America have shown that low birth weight is associated with increased rates of coronary heart disease in adult life (1, 2). Low birth weight is also associated with an increased prevalence of the insulin resistance syndrome, characterized by raised blood pressure, glucose intolerance, and dyslipidemia (3, 4, 5), which is known to predispose to coronary heart disease (6). Although the mechanisms are not known, it has been suggested that resetting of major hormonal axes controlling growth and development may explain these associations (7). Recent studies suggest that subtle abnormalities of the hypothalamic-pituitary-adrenal axis (HPAA) may be of particular importance in linking reduced prenatal growth with the insulin resistance syndrome in adult life. It is well established that environmental exposures in prenatal and early postnatal life may imprint the rodent HPAA, resulting in permanent modification of the neuroendocrine response to stress throughout life (8, 9). Glucocorticoids have potent biological effects, and when present in excess, for example in patients with Cushing’s disease, cause several features of the insulin resistance syndrome, including raised blood pressure, glucose intolerance, and insulin resistance (10, 11, 12). These similarities have led to the suggestion that increased HPAA activity may underlie the development of the insulin resistance syndrome (13). However, the extent to which early growth retardation may affect the HPAA in humans and whether the alterations in HPAA activity could explain the link between reduced fetal growth and the insulin resistance syndrome are not known.

We have studied a sample of men to determine whether low birth weight is associated with increased HPAA activity, as measured by accurately timed, fasting plasma cortisol concentrations, and whether variations in cortisol concentrations within the normal range are linked to insulin resistance, blood pressure, and glucose tolerance.

	Subjects and Methods

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In the county of Hertfordshire, from 1911 onward, midwives who attended the birth of a child recorded the birth weight. Weights were measured in pounds and were often rounded to the nearest half-pound or pound. As previously described (14), we traced 1157 singleton boys born in East Hertfordshire between 1920–1930 who still lived there. Of these, 845 men agreed to be interviewed at home, where their blood pressure was measured with an automated recorder (Dinamap, Critikon, Tampa, FL). Their heights were measured with a portable stadiometer, and their weights were measured with a portable (SECA Ltd, Birmingham, UK) scale. The ratio of waist to hip circumference was recorded as a marker of central obesity. The father’s occupation was used to define social class at birth, and current social class was derived from the subject’s own occupation. Smoking habits and alcohol consumption were recorded. After the home visit, the men were asked if they would be willing to attend a local clinic between 0900–0930 h in the morning after an overnight fast for a standard 75-g oral glucose tolerance test. Among the 370 men who had complete measurements for all blood samples, 66 had impaired glucose tolerance, and 27 had diabetes (14). In addition, 95 were receiving treatment with antihypertensive drugs.

We assayed cortisol in the 0900 h fasting plasma samples by RIA (15), which had an interassay coefficient of variation of between 7.4–10.3%. We measured corticosteroid-binding globulin (CBG) with a commercial assay (Medgenics Diagnostics, Fleurus, Belgium). Plasma free cortisol concentrations were estimated by the ratio of cortisol to CBG. Plasma glucose, insulin, proinsulin, 32–33 split proinsulin, high density lipoprotein cholesterol, and triglyceride concentrations were measured as we have previously described (14, 16). Homeostasis model assessment was used as an index of insulin resistance (17). The sum of the fasting insulin, proinsulin, and 32–33 split proinsulin concentrations was used to estimate the total immunoreactive insulin concentrations required in this model (18). The measurements of glucose, insulin, and triglycerides were transformed to normality using logarithms. Linear regression was used to examine the association between cortisol, birth weight, blood pressure, plasma glucose, insulin, and lipids. P refer to analyses using continuously distributed variables.

	Results

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In this sample of men, aged 59–70 yr (mean, 64 yr), the 0900 h fasting plasma cortisol concentration ranged from 112–702 nmol/L (mean, 344; SD = 112), whereas plasma CBG concentrations ranged from 23.5–86.3 mg/L (mean, 36.6; SD = 5.5). Table 1 shows that higher plasma cortisol concentrations were associated with older age and lower body mass index, but not with the waist to hip ratio. Cortisol concentrations were not associated with smoking, alcohol consumption, or social class, whether defined currently or at birth. Higher plasma cortisol concentrations were associated with higher systolic blood pressure, higher plasma glucose concentrations (fasting and 120 min after oral glucose), insulin resistance, and higher plasma triglyceride concentrations (Table 1). High density lipoprotein cholesterol concentrations fell with increasing cortisol concentrations, although this was not statistically significant (P = 0.06). These associations persisted after adjustment for age and body mass index. The trends with free plasma cortisol concentrations were similar to those with cortisol. There was no trend in low density lipoprotein concentrations with cortisol.

	Discussion

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Our data are in accord with the results of animal experiments that suggest that the HPAA can be reset by transient environment stimuli occurring during prenatal life. Thus, for example, studies of pregnant rats exposed to a variety of stressors, including low protein diets, restraint, alcohol, or nonabortive maternal infections, have shown that the offspring have increased HPAA activity with increased stress-induced corticosteroid secretion in adult life (9, 19, 20, 21). It is thought that these effects are mediated by excessive fetal glucocorticoid exposure, which results in persisting alterations in the activity of the HPAA. In rats, fetal growth retardation induced by dexamethasone leads to permanently increased activity of the HPAA with increased circulating concentrations of corticosterone (22). These changes in the axis are probably effected by a reduced number of glucocorticoid receptors in the hippocampus, which is an important site of negative feedback control (9, 23). The human evidence for this phenomenon, however, is limited to the observations that low birth weight babies have elevated cortisol concentrations in umbilical cord blood and elevated excretion of glucocorticoid metabolites in childhood (24, 25).

Although Cushing’s syndrome and glucocorticoid treatment are known to increase blood pressure and cause glucose intolerance (10, 11, 12), less is known about the effects of physiological variations in plasma cortisol concentrations. Certainly there is good evidence that cortisol concentrations similar to those observed during hypoglycemia, stress, or serious illness (>900 nmol) impair both insulin-mediated suppression of hepatic glucose output and stimulation of glucose uptake (11) as well as enhance lipolysis (26). Our findings suggest that higher cortisol concentrations within the normal range are associated with raised blood pressure, impaired glucose tolerance, insulin resistance, and raised serum triglyceride levels. Previous studies have shown positive correlations between morning plasma cortisol concentrations and fasting insulin concentrations in women (27) and blood pressure in men (28). In contrast, the insulin resistance and hyperinsulinemia of subjects with central obesity is associated with either normal or lower fasting morning plasma cortisol concentrations, albeit with increased urinary cortisol excretion (29, 30, 31, 32, 33). Our finding of an inverse relationship between plasma cortisol concentrations and current body mass index also agrees with these studies. It may be that the strength of the relationship between plasma cortisol concentrations and carbohydrate metabolism is dependent on a balance of the opposing effects of early programming vs. later obesity. Restricted fetal growth is associated with high cortisol levels, whereas adult obesity, which exacerbates insulin resistance, is associated with lower cortisol levels.

Other factors may also influence cortisol levels. By analogy with primate studies (34), which show that subordinate wild baboons have higher circulating glucocorticoid concentrations, it has been suggested that a low position in the social hierarchy, in particular a low level of control at work, and the resulting increased neuroendocrine reactivity and cortisol secretion may contribute to increased risks of cardiovascular disease (35). In the present study, however, we found no association between cortisol concentration and social class whether defined currently or at birth. This suggests that biological factors and, in particular, events in early life may be more potent modulators of the HPAA than the adult social environment.

A single fasting morning plasma cortisol concentration, even when accurately timed, is an imprecise measure of HPAA activity. Our findings are, therefore, all the more remarkable and may have underestimated the strength of the associations. However, we believe that the relationships were observed because of the large size of the study and the careful timing of samples. Our study comprised men who had complete health visitor records, who were traced and still lived in East Hertfordshire, and who were willing to take part in the study. We traced 75% of the men despite the lapse of more than 60 yr. There was no difference in the mean birth weight between men who were traced and not traced or between those who agreed to take part and those who did not. The analysis was based on internal comparisons, and bias would only be introduced if the relation between early growth and subsequent plasma cortisol concentrations differed between those who agreed to take part and those who did not; this is unlikely.

Although our observations are consistent with the hypothesis that the association between impaired fetal growth and the insulin resistance syndrome or coronary heart disease is mediated by programming of the HPAA with increased cortisol production (36), they do not establish the mechanism of the difference in plasma cortisol concentrations. Our data could be explained by alterations in the central drive to CRH secretion, altered feedback responsiveness to glucocorticoids, or alterations in cortisol metabolism. Moreover, the importance of an increased circulating level of cortisol depends on the sensitivity of peripheral tissues to cortisol. We have suggested previously that sensitivity to glucocorticoids is increased in patients with hypertension (37), and more recent data suggest that subjects with increased cortisol secretion in association with multiple cardiovascular risk factors have, if anything, increased tissue sensitivity to glucocorticoids (38). Further detailed studies of the HPAA and of glucocorticoid action in subjects of known birth measurements will determine the nature of the long term changes in glucocorticoid secretion associated with reduced fetal growth.

	Acknowledgments

 
We are grateful to C. Glenn for technical assistance.

	Footnotes

 
¹ This work was supported by the Medical Research Council, the British Heart Foundation, and Lilly Industries.

Received August 14, 1997.

Revised October 20, 1997.

Accepted December 2, 1997.

	References

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				E. Kanitz, W. Otten, and M. Tuchscherer Changes in endocrine and neurochemical profiles in neonatal pigs prenatally exposed to increased maternal cortisol. J. Endocrinol., October 1, 2006; 191(1): 207 - 220. [Abstract] [Full Text] [PDF]

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				D. Qi, D. An, G. Kewalramani, Y. Qi, T. Pulinilkunnil, A. Abrahani, U. Al-Atar, S. Ghosh, R. B. Wambolt, M. F. Allard, et al. Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E420 - E427. [Abstract] [Full Text] [PDF]

				A. Jones, K. M. Godfrey, P. Wood, C. Osmond, P. Goulden, and D. I. W. Phillips Fetal Growth and the Adrenocortical Response to Psychological Stress J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1868 - 1871. [Abstract] [Full Text] [PDF]

				D. I. W. Phillips and A. Jones Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses? J. Physiol., April 1, 2006; 572(1): 45 - 50. [Abstract] [Full Text] [PDF]

				T. Chandola, E. Brunner, and M. Marmot Chronic stress at work and the metabolic syndrome: prospective study BMJ, March 4, 2006; 332(7540): 521 - 525. [Abstract] [Full Text] [PDF]