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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0851
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4340-4345
Copyright © 2007 by The Endocrine Society

Relationships of Urinary Adrenal Steroids at Age 8 Years with Birth Weight, Postnatal Growth, Blood Pressure, and Glucose Metabolism

John W. Honour, Richard Jones, Sam Leary, Jean Golding, Ken K. Ong and David B. Dunger

Department of Clinical Biochemistry (J.W.H.), University College London Hospitals, London W1T 4EU, United Kingdom; Department of Community Based Medicine (R.J., S.L., J.G.), University of Bristol, Bristol BS13NY, United Kingdom; Department of Paediatrics (K.K.O., D.B.D.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; and 4 MRC Epidemiology Unit (K.K.O.), Cambridge CB2 0QQ, United Kingdom

Address all correspondence and requests for reprints to: Dr. John W. Honour, Clinical Biochemistry, University College London Hospitals, 60 Whitfield Street, London W1T 4EU, United Kingdom. E-mail: john.honour{at}uclh.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Introduction: Overactivity of the hypothalamic-pituitary-adrenal axis through a program set by early growth patterns is hypothesized to lead to central obesity, insulin resistance, and hypertension. We therefore examined links between adrenal steroid production and birth weight, rapid early growth, and body mass index (BMI), blood pressure, waist circumference, and resistance to insulin in early childhood through the action of adrenal steroids.

Methods: Timed overnight urine samples were collected in 461 children from a large representative birth cohort. In total 244 boys and 188 girls aged 8.2–8.4 yr completed the protocol. The excretion rates of individual steroids were measured to determine total androgen and cortisol metabolites. Indices of activity of 5{alpha}-androgen reduction of androgens and cortisol metabolites and 11ß-hydroxy steroid dehydrogenase activity were calculated.

Results: In both boys and girls, total urinary androgen and cortisol metabolites were positively related to current height, weight, BMI, and waist circumference. Girls had higher urine androgen metabolite levels and 5{alpha}-androgen indexes than boys, and in girls higher androgen metabolite excretion was associated with lower birth weight and faster postnatal weight gain. After adjustment for current BMI, total cortisol metabolites and 11ß-hydroxy steroid dehydrogenase index were not related to birth weight or postnatal weight gain in either sex.

Conclusions: These data confirm early growth associations in this cohort seen with plasma levels of adrenal androgens at age 8 yr, at least in girls. Larger studies and follow-up during puberty are needed to exclude the possibility of programming of cortisol metabolism by early growth.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AN INCREASED PREVALENCE of risk factors for adult disease including high blood pressure (1, 2, 3), central obesity (4), and reduced insulin sensitivity (5, 6) has been noted in children in relation to size at birth and postnatal growth rates. In children, as in adults, these observations are best seen when current weight is taken into account, indicating a link with the sequence of low birth weight, postnatal catch-up growth, and subsequent risk of obesity (7). The mechanisms underlying these associations are largely unknown (8). From animal experiments it has been proposed that a reduced supply of nutrients from the placenta to the fetus may result in permanent programming of metabolism that persists postnatally (9). The postulated targets of such programming have included hepatic morphology, pancreatic ß-cell development, and the hypothalamic-pituitary-adrenal (HPA) axis.

The HPA axis is a good candidate for prenatal programming because overactivity of that axis can result in insulin resistance, central obesity, and elevated blood pressure. Fetal exposure to glucocorticoids retards fetal growth (10) and in animals can permanently alter the activity of the HPA axis and result in increased blood pressure in adulthood (11, 12). Fetal exposure to maternal glucocorticoids is regulated by placental 11ß-hydroxysteroid dehydrogenase (11ßHSD) type 2, which converts active glucocorticoids (e.g. cortisol) to inert 11-keto forms (e.g. cortisone), and low or inhibited 11ßHSD 2 activity is associated with low birth weight (13). There is some evidence for such links between birth weight and the HPA axis in humans during adult life (see Ref. 14 for review of published studies). In two groups of men and women from Adelaide, Australia (aged 20 yr), and Preston, United Kingdom (46–54 yr), and in a third group of men and women in East Hertfordshire, United Kingdom (60–71 yr), early morning fasting cortisol concentrations fell with increasing birth weight (15). These birth weight associations were independent of age and body mass index, were not associated with changes in cortisol binding globulin (16), and have recently been confirmed with ACTH-stimulated cortisol levels (17). However, other data in humans do not support application of the animal models to man. Dexamethasone has been used to suppress the adrenal gland of the female fetus known to have congenital adrenal hyperplasia. High doses of dexamethasone are used, but birth weights of these infants have been normal (18). Other steroids given to humans have been associated with reductions in birth weight (19).

The HPA axis has not been extensively investigated in children in relation to size at birth and early weight gain. We (20) recently reported that plasma adrenal androgen levels at age 8 yr were independently related to size at birth and current weight, but we did not identify any associations with plasma cortisol levels. However, a single fasting blood sample, as used in that study, may not accurately reflect the dynamics of either cortisol or adrenal androgen secretion. Frequent blood sampling or urinary excretion of cortisol and adrenal metabolites may give a much better index of steroid output (21). Urinary total cortisol metabolites provide a measure of daily cortisol production, which is close to that obtained with gold standard stable isotope techniques (22). The urinary chromatographic data can also establish the ratio of cortisol to cortisone metabolites, thus providing an index of 11ßHSD types 1 and 2 activities as well as providing parallel assessment of adrenal androgen production.

To date, only one small study of 9-yr-old children from Salisbury, United Kingdom, has looked at the relationship between total urinary cortisol metabolites and birth weight. In that study a quadratic U-shaped relationship was observed between birth weight and total urinary cortisol metabolites (23), but no other analyses were carried out on the ratio of cortisol to cortisone metabolites or adrenal androgen metabolites. Thus, the aim of the present study was to assess adrenal function in timed urine collections from a large representative cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). We carried out full urinary chromatographic analyses in timed overnight urine samples and sought associations with birth weight, early weight gain, current weight, arterial blood pressure, and insulin sensitivity, using data already available in the ALSPAC cohort.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The ALSPAC birth cohort includes 14,062 live births, comprising over 80% of all births in the three Bristol-based District Health Authorities between April 1991 and December 1992. Children were measured at birth by the research study team and detailed information on infant feeding and a large number of social and environmental data but not abnormalities in pregnancy were collected by interview and questionnaire. Most infants were born at term. A 10% subcohort (Children in Focus) was randomly selected from the tail end of births in ALSPAC to undergo regular postnatal measurements (at 4, 8, 12, 18, 24, 31, 37, 43, 49, and 61 months). Comparison with U.K. 1990 growth references show that this Children in Focus cohort is representative in terms of birth weight (mean U.K. reference SD score = 0.0, SD = 1.0) (24). In an additional subset of children (control group), direct measurements of growth are also available from early childhood. Together these subsets consist of approximately 1800 children. The whole cohort has attended annual half-day clinics from the age of 7 yr. This subset has been directly examined at various times since birth so that detailed growth data (including records of height, weight, and waist measurements) and blood pressure measured at 3.5, 7, and 9 yr are available.

Data collection

Eight hundred fifty ALPSAC children from these two subcohorts were examined at age 8 yr for assessment of anthropometry, fasting blood collection for insulin, glucose and lipid profiles, and oral glucose tolerance. Pubertal staging was not undertaken formally to limit medical interventions during the course of ALSAC. On the basis of normal birth weights, few children from pregnancies complicated by preeclampsia, gestational diabetes and small for gestational age (SGA) were likely to have been included in the group. In all children, detailed information on pregnancy, size at birth, and early growth patterns have been collected, and the children are also being assessed for: 1) anthropometric parameters, with the children being assessed for height, weight, and waist circumference at age 8 yr; and 2) arterial blood pressure recorded at 7 and 9 yr of age using a Dinamap 9300 automated Vital Signs monitor (Critikon, Tampa, FL) and an appropriate size cuff on two occasions (and the average taken). Times of day and ambient room temperature were recorded as potential confounding factors that influence blood pressure.

Insulin sensitivity was calculated from fasting glucose and insulin concentrations using the homeostasis model (25). Insulin secretion was calculated as change in insulin divided by the change in glucose over 30 min after an oral glucose load (26).

Timed urine collections were obtained at age 8 yr. Urine collection for 14 h, from 2200 to 1200 h the following day, is not difficult, provided that the children understand and adhere to instructions. Collections were judged to be reliable when total volumes were between 300 and 750 ml and the creatinine concentrations were within the range 3.5 to 15 mmol/liter (27). Other samples were not processed for steroid excretion rates due to the likelihood of incomplete collections. Samples were collected in plain containers and aliquots stored at –20 C until analysis. Ethical approval was obtained from the ALSPAC and local research ethics committees. Signed consent was obtained from a parent and verbal consent was obtained from the child.

Urine steroid metabolite excretion rates were measured in 461 frozen urine samples from the sample of 288 boys and 173 girls who had fasting glucose, lipids, and insulin levels measured, and oral glucose tolerance and insulin response assessed, at 8 yr of age. Children taking any form of steroid medication in the past year were excluded from the present study. Steroids in urine were analyzed by gas chromatography after solid phase extraction, enzyme hydrolysis of conjugates, and derivative formation (methyloxime-trimethylsilyl ether) (28). A capillary column was used in the gas chromatograph for optimal resolution, and a flame ionization detector was used as the detector for the quantitative analysis. Steroids were confirmed by separate analysis using gas chromatography coupled to a mass spectrometer. A total cortisol metabolite excretion rate was obtained from the sum of results for 11-hydroxyandrosterone, 11-hydroxyaetiocholanolone, tetrahydrocortisone, tetrahydrocortisol (THF) allo-THF, {alpha}- and ß-cortolone, and {alpha}- and ß-cortol. Androsterone, etiocholanolone, and dehydroepiandrosterone in urine were added together for an adrenal androgen index. We determined a ratio from THF plus allo-THF divided by tetrahydrocortisone, which reflects the activity of 11ßHSD. The method has been fully validated with respect to recovery and imprecision. The within-individual coefficient of variation for total cortisol metabolite is 7.6 and 10–13% between individuals.

Data analyses

Ponderal index at birth was calculated as weight/length3. Body mass index (BMI) at age 8 yr was calculated as weight/height squared. Body weight, BMI, and waist circumference at 8 yr of age showed positively skewed distributions. Internally derived gender and age-appropriate SD scores for each were calculated based on transformed, normally distributed values [SD score = (measurement – population mean)/population SD]. Postnatal weight gain was calculated for 222 boys and 169 girls as change in body weight SD score between birth and 3 yr; a gain in SD score greater than 0.67 was taken to indicate clinically significant catch-up weight gain because 0.67 represents the width of each centile band on standard growth charts (24). Similarly, a decrease in weight SD score between 0 and 3 yr by more than 0.67 indicated catch-down weight growth.

Sex differences were examined by t test of log-transformed variables. Using multiple linear regression, urinary steroid excretion rates in boys and girls separately were analyzed in relation to current weight, height, and BMI, adjusted for age. With further adjustment for current BMI, urinary steroid excretion rates were analyzed in relation to size at birth, weight gain between birth and 3 yr, systolic and diastolic blood pressure, and fasting insulin sensitivity and insulin secretion after oral glucose. Results of linear regression models are displayed as standardized regression coefficients (ß-coefficients). Analyses were performed using SPSS (version 11; SPSS Inc., Chicago, IL).

The sample size of around 200 boys and 200 girls was predicted to allow detection of differences in urinary androgen and cortisol metabolite excretion rates of 0.5 SD for each tertile of distribution at the 0.05% level of significance with 80% power.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Details of the study population are summarized in Table 1Go. The selected children, on the basis of available data, were representative of the other ALSPAC children with regard to size at birth and current weight, height, BMI, and waist circumference at age 8 yr. Levels of total androgen metabolites were higher in girls than boys (Table 2Go) as was the 5{alpha}-androgen activity index. There were no significant gender differences for total cortisol metabolites or other metabolite activity indices.


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  		TABLE 1. Study group demographics and size at birth by gender

 

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  		TABLE 2. Parameters of urine steroid metabolism by gender

 
Total androgen metabolites and total cortisol metabolites in urine were positively related to current height, weight, BMI, and waist circumference in both boys and girls (Table 3Go).


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  		TABLE 3. Correlations between current body size and various parameters of urine steroid metabolism at age 8 yr in boys and girls

 
After adjustment for current BMI, there were no consistent associations observed among size at birth, gestational age (data not shown), and adrenal function at age 8 yr (Table 4Go and Fig. 1Go). In girls, but not boys, total androgen metabolites were positively related to early postnatal weight gain between 0 and 3 yr (Table 4Go and Fig. 2Go). Indices of steroid enzyme activity (5{alpha}-androgen, 5{alpha}-cortisol, and 11ßHSD) were not related to birth weight or postnatal weight gain in either group (Table 4Go). After adjustment for current BMI, there were no significant associations between arterial blood pressure, insulin sensitivity, or insulin secretion with any measure of urinary steroid production in either boys or girls (data not shown).


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  		TABLE 4. Correlation between size at birth and early postnatal weight gain and various parameters of urine steroid metabolism at age 8 yr in boys and girls (adjusted for current BMI)

 

Figure 1
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  		FIG. 1. Total urine cortisol metabolite levels (mean + 95% confidence interval) at age 8 yr according to birth weight. Boys are shown in gray bars, girls in white bars. No significant associations with birth weight were seen.

 

Figure 2
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  		FIG. 2. Total urine androgen metabolite levels (mean + 95% confidence interval) at age 8 yr were associated with early postnatal weight gain in girls (white bars; *, P trend < 0.05) but not boys (gray bars; P = 0.9).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We previously reported that lower birth weight and rapid early postnatal weight gain are related to obesity and insulin resistance risks in 8-yr-old children in this ALSPAC cohort (24, 29). We also reported higher plasma adrenal androgen levels in relation to both lower birth weight and rapid postnatal weight at age 8 yr but no differences in fasting plasma cortisol levels (20). Some papers show correlations of low birth weight with high serum dehydroepiandrosterone sulfate of in appropriate-for-gestational-age-born and SGA-born children (30), but others did not find this link (31). Increase in dehydroepiandrosterone sulfate at 12 yr was demonstrated in SGA-born children (32). Our findings are now replicated in the present study using timed urinary steroid profiles, which provide a measure of adrenal steroid production. Urinary cortisol and androgen metabolites were positively related to current size. In girls, but not boys, urinary androgen metabolites were positively related to early postnatal weight gain. Higher excretion rate of androgens in urine of girls is consistent with the differences in the usual timing of adrenarche. As in our study of plasma steroid levels (20), we were not able to demonstrate any relationship between urinary markers of cortisol metabolism and size of birth or postnatal weight gain. Most infants were born near term so relationships with gestational age were not tested, so effects of intrauterine environment on HPA function (33, 34) are unlikely.

There is convincing animal experimental data linking prenatal programming to persisting over activity of the HPA axis in association with insulin resistance, central obesity, and elevated blood pressure (10, 11, 12). Data from adult studies also show associations between birth weight and basal or stimulated cortisol levels (17), and in three studies, there appeared to be an inverse relationship between fasting cortisol levels and increasing birth weight (15). However, other studies in nonstress situations failed to show a relationship between birth weight and fasting cortisol levels (35, 36), salivary cortisol levels on awakening, and dynamic tests of the HPA axis with corticotrophin-releasing factor (37). Similarly, in the present study, we were unable to detect any association between total cortisol metabolites and birth weight, postnatal weight gain, insulin sensitivity, or blood pressure.

Measurements of cortisol and androgen metabolites in the urine provide much better estimates of cortisol and androgen production rates than do static measurements of blood plasma levels (38, 39). They also permit analysis of urinary metabolite ratios, which can give estimates of key enzyme activities, such as 11ßHSD. The placental form of this enzyme regulates fetal exposure to maternal glucocorticoids, and in animal studies, lower or inhibited 11ßHSD activity was associated with low birth weight (40). Persisting postnatal variation in expression of this enzyme could be associated with the features of the metabolic syndrome, but we found no evidence of early growth associations with 11ßHSD activity in the urine samples from our children aged 8 yr.

The relatively small sample size reduced the power to detect differences in urinary androgen and cortisol metabolite excretion of the order of 0.5 SD between subgroups. It is unlikely that changes in metabolites of a lower order would have significant metabolic relevance; however, even minor differences in estimated cortisol and androgen production over 14 h could lead to a significant cumulative exposure over several years of childhood development. In adults (41), it has recently been shown that maximal excretion of steroid metabolites in urine extends beyond midday, when we ended our urine collections. Children may have an earlier peak in metabolite excretion rates. The ratio of cortisol to cortisone metabolites does not vary appreciably over 24 h. Furthermore, we did not test hormone levels under stress conditions, and some studies in children and adults suggest that subjects with low birth weight may have higher stimulated cortisol responses (42). Finally, it is possible that differences in the HPA axis as they relate to cortisol production may become evident only during puberty, and follow-up studies during adolescence are needed to exclude the possibility of programming of cortisol metabolism by early growth.


   Acknowledgments
 
We are extremely grateful to all the families who took part in this study; the midwives for their help in recruiting them; and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. We appreciate the skilled assistance of Bezhad Delavari, who undertook the urine steroid profile analysis.


   Footnotes
 
This work was partly supported by the British Heart Foundation. The U.K. Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC. D.B.D. is supported by the Wellcome Trust and the Juvenile Diabetes Research Foundation.

Disclosure Statement: The authors have nothing to declare.

First Published Online August 28, 2007

Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; BMI, body mass index; HPA, hypothalamic-pituitary-adrenal; 11ßHSD, 11ß-hydroxysteroid dehydrogenase; SGA, small for gestational age; THF, tetrahydrocortisol.

Received April 16, 2007.

Accepted August 17, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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