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Fetal Programming of the Hypothalamic-Pituitary-Adrenal (HPA) Axis: Low Birth Weight and Central HPA Regulation

Medical Research Council Environmental Epidemiology Unit (A.M.V.W., H.E.S., D.I.W.P.) and Regional Endocrine Laboratory (P.J.W.), Southampton General Hospital, Southampton, SO16 6YD, United Kingdom; and Pediatric and Reproductive Endocrinology Branch (G.P.C.), National Institute of Child Health and Human Development, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Prof. David I. W. Phillips, Medical Research Council Environmental Epidemiology Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, United Kingdom.

	Abstract

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Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an intermediary in the association between reduced fetal growth and adult cardiovascular and metabolic diseases. Previous studies have shown that small size at birth is associated with increased fasting plasma cortisol and adrenal responsiveness to ACTH stimulation. We have extended these studies by evaluating the salivary cortisol response to awakening and plasma ACTH and cortisol responses to CRH stimulation and a dexamethasone-suppressed CRH (DEX/CRH) test in a group of low birth weight [LBW; <3.18 kg (7 lb), n = 58] and high birth weight [>3.86 kg (8.5 lb), n = 65] men aged 60–69 yr. Despite no difference in basal pituitary-adrenal activity or in their ACTH and cortisol responses to CRH, LBW men had significantly lower pituitary-adrenal responses in the DEX/CRH test. Although these findings do not explain the HPA abnormalities associated with LBW in previous studies, they provide further evidence of dysregulation of the HPA axis in people who were small at birth.

	Introduction

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EPIDEMIOLOGICAL STUDIES HAVE provided a large body of evidence linking low birth weight (LBW) or thinness at birth with adult cardiovascular disease and its biological forerunners, hypertension, impaired glucose tolerance, and insulin resistance (the metabolic syndrome) (1). This phenomenon may be explained by programming, a process whereby a stimulus or insult at a critical period in development results in permanent adaptation of the organism’s structure or physiology. Recent studies have suggested that fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis may be one of the long-term changes that link reduced fetal growth with adult metabolic disease. In animal models, prenatal stress, maternal malnutrition, or glucocorticoid exposure in pregnancy have produced offspring with alterations of either basal or stimulated HPA activity and lifelong hypertension or glucose intolerance (2, 3, 4, 5). Preliminary human studies have shown an inverse association between birth weight and both fasting 0900 h cortisol concentration and adrenal responsivity to ACTH (6, 7). Following animal data suggesting a central origin for the HPA alterations induced by adverse prenatal events, we hypothesized that hypercortisolemia in people who were small at birth was due to increased hypothalamic secretion of CRH. A similar abnormality has been suggested in depressed patients (8).

In the current study, we have evaluated the central regulation of the HPA axis by measuring the postwakening rise in cortisol concentrations and by comparing responses to CRH-stimulated pituitary-adrenal activity in LBW and high birth weight (HBW) men recruited from a birth cohort in Hertfordshire, United Kingdom. The majority was further examined by means of a dexamethasone-suppressed CRH (DEX/CRH) test.

	Subjects and Methods

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Study population

From 1911–1948, detailed infant records, including birth weight and weight at 1 yr, were collated in the county of Hertfordshire, United Kingdom. Early data supporting the fetal origins hypothesis were collected from individuals born before 1930 who were traced from these records (9, 10). In 1998, the Medical Research Council Environmental Epidemiology Unit in Southampton began recruiting a younger cohort to participate in studies examining the interactions between early life, adult diet, and lifestyle and genetics as determinants of adult disease. One thousand three hundred ninety-seven men born between 1931 and 1939 and still living in East Hertfordshire were traced with the aid of the National Health Service central registry in Southport and were contacted with their General Practitioner’s permission. Of these individuals, 737 (53%) agreed to take part in the new Medical Research Council study. [Five graded social class groupings were used: I, professional; II, employers and managers; III, skilled occupations (NM, nonmanual; and M, manual); IV, partly skilled; and V, unskilled occupations]. Detailed information on their medical history, socioeconomic status, exercise patterns, and smoking and alcohol consumption was obtained from a nurse-administered questionnaire. Mood was assessed with the Hospital Anxiety and Depression (HAD) scale (11), and anthropometry (height, weight, waist and hip circumferences, and skinfold thickness at four sites) was carried out.

From this cohort, individuals in the top [HBW, >3.86 kg (8.5lb)] and bottom [LBW, <3.18 kg (7 lb)] quartiles of birth weight were approached to participate in the HPA programming study. A factorial design was decided upon to increase the power of the study given the time and expense involved in CRH testing. A sample size of 102 was necessary to detect a 30% difference in the ACTH response to CRH between the groups with 80% power at the 5% significance level [based on a mean ACTH response (incremental area under the curve) of 115 pmol/min·liter; SD, 63 pmol/min·liter] (12). At the start of recruitment for the current study, 597 men had completed the baseline assessment; 145 men were in the bottom quartile of birth weight, and 139 were in the top quartile of birth weight. Permission was once again sought from general practitioners, and individuals were excluded if they had a history of pituitary or adrenal disease, diabetes, or either major depression or glucocorticoid treatment in the previous 3 months. Two hundred five subjects were available for contact, of whom 122 (60%; LBW, n = 58) were recruited. Ethical approval was obtained from the North and East Hertfordshire Local Research Ethics Committee, and all subjects gave written informed consent.

Salivary cortisol response to awakening

Subjects were sent five Salivettes (Sarstedt, UK) with which to collect saliva. They were asked to fast from midnight and then to collect a saliva sample at 0, 15, 30, 45, and 60 min after waking the following morning. They remained fasting during this period and were asked to refrain from brushing their teeth to prevent contamination of the saliva samples with blood. They brought the samples with them to the clinic.

CRH test

Subjects attended the clinic at 0800 h the same morning. A 21-gauge canula was inserted into an antecubital vein, and the subject then rested for 30 min in a semirecumbent position. Baseline blood samples were drawn at -15 and -5 min before CRH administration. At 0900 h, 100 µg human CRH (Ferring Pharmaceuticals, Slough, UK) was injected as a bolus and flushed through with 10 ml 0.9% saline. Lyophilized CRH was reconstituted in the supplied diluent immediately before administration. Ten-milliliter blood samples were then drawn from the canula at 5, 15, 30, 45, 60, 90, and 120 min. The patency of the canula was maintained with regular saline flushes. Blood for ACTH analysis was collected into chilled EDTA tubes, stored on ice, and spun at 4 C within 20 min, and the plasma was immediately frozen to -80 C until assayed. Serum for cortisol analysis was prepared from clotted samples. After removal of the canula, subjects were given breakfast.

CRH administration resulted in facial flushing in 77% of the subjects. Five men experienced a brief vasovagal episode within 10 min of CRH injection, and two men became unwell during the course of the study. Examination of the ACTH and cortisol response profiles in these subjects showed extremely high values compared with other participants, and therefore, they were excluded from further analysis. The data from a needle phobic subject who had very high baseline values and who failed to respond to CRH were also excluded. Baseline blood samples were accidentally frozen in one subject, rendering them unsuitable for ACTH analysis.

DEX/CRH test

Subjects who completed the CRH test without side effects (n = 115) were invited to attend on a second occasion for a DEX/CRH test. This visit was at least 1 month after the first visit to ensure that the results were not influenced by the CRH test. One hundred three subjects (LBW, n = 46) agreed to take part. They were given 1.5 mg dexamethasone to take at 2300 h on the night before the study and were asked to have breakfast as usual the following morning but to avoid caffeine-containing drinks. They attended the clinic at 1230 h and were given a standard sandwich lunch to ensure that all subjects had equivalent calorie and electrolyte intake before the DEX/CRH test. At 1330 h, a canula was inserted into an antecubital vein, and the subject then rested in a semirecumbent position for 30 min. Baseline blood samples were drawn at -15 and -5 min before injection of 100 µg human CRH. After the injection, blood was sampled at 15, 30, 45, 60, 75, 90, 105, and 120 min for ACTH and cortisol. Samples were prepared as described above. No subject experienced any adverse effect during the DEX/CRH test.

Laboratory methods

All assays were performed under the supervision of Dr. Peter Wood in the Regional Endocrine Laboratory at Southampton General Hospital. Salivary cortisol was measured using a time-resolved fluorescent immunoassay (DELFIA system, Perkin-Elmer Life Sciences, Cambridge, UK). Examination of the interassay precision profile for the salivary cortisol assay showed that the coefficient of variation (CV) was 5–10% between 2 and 15 nmol/liter cortisol. The assay had a lower limit of detection of 0.4 nmol/liter. The cross-reactivity of cortisone in the salivary cortisol assay was 2.5%. Because the mean cortisol to cortisone ratio at this time of day is between 0.32 and 0.48 (13), the contribution of cortisone to the cortisol results was less than 1 nmol/liter. Serum cortisol was assayed using an in-house RIA. An extra-low standard (15.6 nmol/liter) was included to give additional resolution at low concentrations. The interassay CV at this concentration was 14.9% and ranged from 7.4–10.3% within the normal range of cortisol concentrations. Plasma ACTH was measured with a highly sensitive commercial assay (Nichols Institute, San Clemente, CA) to give precise results at low ACTH concentrations. The detection limit of this method is 0.2 pmol/liter, approximately 10 times lower than most conventional ACTH methods. The interassay CV at a concentration of 1.1 pmol/liter was 10.4% and ranged from 6.8–7.8% between 7.9 and 78.8 pmol/liter ACTH.

Statistical analysis

Log_e-transformed ACTH and cortisol values were used where necessary. The integrated salivary cortisol concentration in the first hour after waking [area under the curve (AUC)] was calculated by the trapezoidal rule. The cortisol response to awakening was defined as the incremental AUC (iAUC = AUC-baseline area). Unstimulated, fasting 0900 h cortisol and ACTH concentrations in the CRH test and dexamethasone suppression test (DST) values in the DEX/CRH test were derived from the mean of the two baseline values in each test. The response to CRH stimulation in both tests was defined as the iAUC. The response profiles during the three tests were analyzed extensively using various parameters, including peak, increment, percentage increase, recovery rate, time to peak, and AUC. Because the pattern of the results was similar across these measures, only the iAUC analysis is presented. ACTH iAUC in the CRH test and cortisol and ACTH iAUC in the DEX/CRH test were transformed to normality using Fisher-Yates normal scores because negative values prevented logarithmic transformation. Student’s t tests and regressions were based on these variables, but descriptive statistics (median and interquartile range) are presented on the untransformed scale for simplicity.

Baseline and CRH-stimulated pituitary-adrenal activity in the LBW and HBW groups were compared using the unpaired t tests. The possible confounding effects of age, obesity, smoking and alcohol consumption, and social class were examined using multiple linear regression. The ACTH and cortisol response profiles were also analyzed longitudinally. The longitudinal approach considers the full series of ACTH or cortisol data for each subject and uses a generalized estimating equation to model the average response during the test in relation to the factors of interest, taking into account the effects of time and the autocorrelation of ACTH or cortisol measurements within each subject (14). All analyses were performed using Stata Statistical Software Release 7.0 (Stata Corporation, College Station, TX).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The basic characteristics of the study participants are listed in Table 1. There were no differences in anthropometry, adult lifestyle factors, or metabolic variables between these individuals and the members of the cohort who were eligible for the study but who did not take part. The LBW group had a mean birth weight of 2.8 kg (range, 2.0–3.1 kg), whereas the mean birth weight of the HBW group was 4.3 kg (range, 4.0–5.0 kg). The subjects were between the ages of 60.5 and 69.6 yr in both birth weight groups. The LBW group was significantly shorter and lighter, but there were no differences in any of the obesity measures, social class, smoking status, or alcohol consumption between the two groups. None of the subjects was suffering from depression (HAD score, >10).

View larger version (19K): [in this window] [in a new window]   FIG. 1. ACTH (A) and cortisol (B) responses to 100 µg human CRH in two groups of men differentiated by birth weight. Inset, Peak response during the CRH test. Data are expressed as geometric means ± SEM.

There was no difference in DST result between the two groups; however, both ACTH and cortisol responses to CRH stimulation after dexamethasone were lower in the LBW men (Table 3 and Fig. 2). These differences were not altered by correction for potential confounders. Longitudinal analysis confirmed these findings (P < 0.01), but did not reveal any evidence of a birth weight to time interaction. The awakening response and CRH test analysis was repeated in the subgroup that participated in the DEX/CRH test, but the results were no different from the original group of 122 men who underwent these tests.

View larger version (18K): [in this window] [in a new window]   FIG. 2. ACTH (A) and cortisol (B) responses during a DEX/CRH test in two groups of men differentiated by birth weight. Inset, Peak response during the DEX/CRH test. Data are expressed as geometric means ± SEM.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The salivary free cortisol response to awakening has been proposed as a measure of HPA activity, avoiding the stress of venepuncture (15). Elevated levels are reported in individuals under chronic stress (16). Recently, Edwards et al. (17) have shown that the total integrated free cortisol concentration over the first hour (AUC) is a good correlate of diurnal cortisol rhythm (i.e. basal HPA activity), whereas the cortisol response (iAUC) was not, which further suggests that this measure may be a dynamic test of HPA function. We found no correlations between birth weight and either of these measures. Therefore, these findings add to other published evidence from 24-h profiles of cortisol secretion suggesting that there is no relationship between birth weight and the nonstressed rhythm of cortisol secretion (18, 19).

We also found no significant group differences in the ACTH and cortisol responses to CRH, indicating that, in these LBW men, the corticotroph is functioning normally. Likewise, after dexamethasone, the baseline ACTH and cortisol concentrations were similar between groups. However, the LBW men had significantly lower ACTH and cortisol responses to CRH testing after dexamethasone. Although this could be a chance finding, it was backed up by longitudinal analysis of the data, and differences in peak and increment also bordered on being significant. It is possible that this finding reflects differential dexamethasone metabolism between the two birth weight groups. However, this is thought to be unlikely because there was no difference in dexamethasone concentration after an overnight DST in the highest and lowest birth weight quartiles in a previous study, and correcting for dexamethasone concentration did not alter the birth weight HPA associations in that study (7). In the present study, no patient was taking medication known to influence the activity of hepatic CYP3A4 activity and thus dexamethasone metabolism.

The DEX/CRH test has been developed as a tool to investigate subtle HPA dysfunction, particularly in depression and related pathological conditions. Several studies show that depression is associated with increased CRH responses after dexamethasone (20, 21). Because dexamethasone, a synthetic steroid, does not freely pass the blood-brain barrier, its major target is the pituitary gland (22). It is suggested that the findings in depression imply a decreased pituitary sensitivity to dexamethasone, possibly as a result of increased vasopressin action at the corticotroph, which attenuates the inhibitory effect of glucocorticoids on CRH-stimulated ACTH secretion. Our results may, therefore, reflect the reverse, i.e. increased pituitary sensitivity to dexamethasone or reduced vasopressinergic drive.

Previous studies carried out by ourselves and others have suggested that people who were small at birth have high urinary excretion of glucocorticoids in childhood, raised fasting plasma cortisol concentrations in adult life, and increased adrenal responsiveness to synthetic ACTH administration (6, 7, 23, 24, 25). Because similar abnormalities in melancholic depression are thought to be due to abnormal central regulation of the pituitary-adrenal axis, we hypothesized that the responses to CRH testing would be similar to those seen in depressed patients. However, the pattern we observed bears closer resemblance to the alterations in HPA activity associated with chronic fatigue and atypical depressive syndromes, such as seasonal affective disorder, than with melancholic depression. Although there are no studies using the DEX/CRH test, Demitrack et al. (26) found reduced ACTH and cortisol responses to CRH in patients with chronic fatigue syndrome, which they suggested reflected impaired central drive to the pituitary. Other groups have confirmed these findings, and similar results have been obtained in studies of subjects with seasonal affective disorder (27, 28).

It is possible that earlier findings in individuals who were small at birth reflect a primary abnormality that is not at the level of hypothalamic-pituitary control of adrenal function, such as an increased stress response or an abnormality of peripheral glucocorticoid metabolism. However, in the current study, because we found no differences in basal pituitary-adrenal activity between birth weight groups, our results do not help to explain the hypercortisolemia found in association with LBW previously.

It is not clear why this cohort differs from the older Hertfordshire population in whom there were strong inverse relationships between birth weight and 0900 h cortisol. More detailed studies in the older cohort did not find that diurnal HPA activity was related to birth weight (18). One interpretation of these conflicting results is that antenatal events resulting in small size at birth program stress responses rather than basal HPA activity because it is possible that 0900 h cortisol determinations taken in a novel clinic setting may better reflect stress responsiveness. Thus, the presence or absence of a relationship with a single cortisol measurement may depend on the circumstances in which the sample was taken.

In addition, birth weight is a crude indicator of antenatal exposures, and in both animal and human studies, prenatal insults have been shown to affect HPA activity independently of birth weight. A good example of this has recently been found in a group of young Scottish adults who have become a unique resource for investigating the impact of extreme dietary manipulation in human pregnancy. Their mothers were advised to eat a high protein (1 lb of red meat per day), low carbohydrate diet. In this cohort, there was no association between birth weight and fasting morning cortisol, but higher meat and/or fish intake in late pregnancy was associated with raised cortisol concentrations at 30 yr of age (29). Future studies in this field will be aided by prospective cohorts for which detailed data has been collected before, during, and after pregnancy.

In conclusion, this study adds to the evidence that LBW is associated with subtle abnormalities of HPA function but does not explain the alterations in HPA activity that have been previously reported to be associated with LBW.

	Acknowledgments

 
We are extremely grateful to the Hertfordshire Cohort Study Group whose work in creating this valuable new cohort enabled the present study. We also thank Carmel Judge for her assistance during the studies and Christine Glenn for performing the assays. Finally, we are indebted to the men who participated.

	Footnotes

 
Supported in part by National Institutes of Health Grant 1 R01 HD41107-01 (to D.I.W.P.).

Abbreviations: AUC, Area under the curve; CV, coefficient of variation; DEX/CRH, dexamethasone-suppressed CRH; DST, dexamethasone suppression test; HAD, Hospital Anxiety and Depression; HBW, high birth weight; HPA, hypothalamic-pituitary-adrenal; iAUC, incremental AUC; LBW, low birth weight.

Received June 5, 2003.

Accepted November 24, 2003.

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