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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2647-2651
Copyright © 2004 by The Endocrine Society

Obesity: Original Article

Opposing Influences of Prenatal and Postnatal Weight Gain on Adrenarche in Normal Boys and Girls

Ken K. Ong, Neus Potau, Clive J. Petry, Richard Jones, Andrew R. Ness the Avon Longitudinal Study of Parents Children (ALSPAC) Study Team, John W. Honour, Francis de Zegher, Lourdes Ibáñez and David B. Dunger

Department of Paediatrics (K.K.O., C.J.P., D.B.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Hormonal Laboratory (N.P.), Hospital Materno-Infantil Vall d’Hebron, E-08035 Barcelona, Spain; Unit of Paediatric and Perinatal Epidemiology (R.J., A.R.N., ALSPAC Study Team), University of Bristol, Bristol BS8 1TQ, United Kingdom; Department of Chemical Pathology (J.W.H.), University College London Hospitals, London W1T 4JF, United Kingdom; Department of Paediatrics (F.d.Z.), University of Leuven, B-3000 Leuven, Belgium; and Endocrine Unit (L.I.), Hospital Sant Joan de Déu, University of Barcelona, E-08950 Barcelona, Spain

Address all correspondence and requests for reprints to: Professor David B. Dunger, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Level 8, Box 116, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Associations between low birth weight and higher adrenal androgen secretion before puberty have yet only been reported in case-control studies in girls. We examined the influence of birth weight and early postnatal weight gain on overnight-fasting adrenal androgen and cortisol levels in 770 children from a large normal United Kingdom birth cohort at age 8 yr. In univariate analyses, adrenal androgen levels were inversely related to birth weight SD score in each sex [dehydroepiandrosterone sulfate in boys: regression coefficient (B) = –2.5 µg/dl/SD; 95% confidence interval (CI), –4.7 to –0.2; in girls: B = –3.8 µg/dl/SD; 95% CI, –6.2 to –1.4; androstenedione in boys: B = –0.15 nmol/liter/SD, 95% CI, –0.25 to –0.6; in girls: B = –0.13 nmol/liter/SD; 95% CI, –0.24 to –0.02). In multivariate analyses, both lower birth weight and larger current body weight predicted higher adrenal androgen levels (P < 0.005 for all comparisons). Allowing for current weight, children who showed rapid postnatal weight gain between 0 and 3 yr had higher dehydroepiandrosterone sulfate (P = 0.002) and androstenedione (P = 0.004) levels at 8 yr. In contrast, cortisol levels were unrelated to birth weight or current body size. In summary, the relationship between lower birth weight and higher childhood adrenal androgen levels was continuous throughout the range of normal birth weights, and was similar in boys and girls. Adrenal androgen levels were highest in small infants who gained weight rapidly during early childhood. We suggest that higher adrenal androgen secretion could contribute to links between early growth and adult disease risks, possibly by enhancing insulin resistance and central fat deposition.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LOWER BIRTH WEIGHTS are related to higher risks for adult disease, such as type 2 diabetes and cardiovascular disease (1). It has been suggested that these links could result from programming of a number of metabolic pathways, including those for insulin and cortisol (1, 2). In girls, low birth weight has been associated with early and exaggerated adrenal androgen secretion before puberty (premature adrenarche), a condition that predicts later ovarian hyperandrogenism and is related to a constellation of disease risk markers such as insulin resistance and dyslipidemia (3, 4, 5). Increased early androgen production might therefore represent an additional mechanism that contributes to the association between lower birth weight and increased disease risk.

To date, those findings with adrenal androgen levels have only been observed in case-control studies in girls, but not boys, who were identified either because they had low birth weight (<–2 SD) (4) or because they presented with precocious pubarche (3), defined as the onset of pubic hair before age 8 yr secondary to early adrenarche. In contrast, the association between size at birth and adult disease is continuous throughout the range of normal birth weights and is seen in both males and females. We therefore examined the association between size at birth and early childhood growth on adrenal androgen and cortisol levels in a large unselected population-based study of children at age 8 yr.


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

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective study of 14,541 pregnancies recruited from all pregnancies in three Bristol-based District Health Authorities with expected dates of delivery between April 1991 and December 1992 (6). Children from two randomly selected subcohorts ("children in focus," n = 1335; and "control cohort," n = 1000) had growth measurements at age 3 yr. Details of antenatal data collection and measurement of body size from birth to 5 yr by the ALSPAC study team have been previously described (7), and further details are available on the ALSPAC web site (http://www.alspac.bris.ac.uk).

Eight hundred fifty-one unselected full-term (>=37 wk gestational age), singleton children from these two subcohorts attended a research clinic and gave a fasting blood sample and had body size measurements taken at age 8 yr. Of these, 770 subjects had sufficient plasma samples for adrenal androgen assays, and all analyses in this paper are based on this group. These children did not differ from other ALSPAC children with regard to body size at birth or during childhood.

Data were excluded on children who were taking oral steroids (n = 1) or who admitted to be nonfasting on the questionnaire (n = 2). Eighteen children were taking inhaled steroids; they had no differences in cortisol or adrenal androgen levels compared with other children, and they did not differ by birth weight, weight gain at 0–3 yr, or current weight. An additional 18 children were nonwhite; compared with white children, they showed no differences in cortisol or adrenal androgen levels, nor in birth weight, weight gain at 0–3 yr, or current weight.

Approval was obtained from the ALSPAC ethics and law committee and the local research ethics committees. Signed consent was obtained from a parent, and verbal assent was obtained from the child.

Fasting blood samples

At age 8 yr (mean ± SD age, 8.2 ± 0.1 yr; range, 8.0–8.5 yr), children attended the research clinic in the morning (mean ± SD time, 0850 h ± 22 min; range, 0806–1030 h) after fasting from at least midnight the previous day. Body weight was measured using electronic scales, standing height was measured by stadiometer (Leicester height measure, Child Growth Foundation, London, UK), and waist circumference was measured midway between the lowest rib and the iliac crest by tape measure (Harpenden anthropometric tapes, Holtane Ltd., Crosswell, Dyfed, UK). A venous blood sample was collected after application of topical analgesic cream (EMLA cream, AstraZeneca, London, UK). All samples were placed immediately onto ice, centrifuged within 30 min, and stored at –70 C until assay.

Assays

Androstenedione was measured using a solid-phase RIA (DSL, Oxford, UK). Intra- and inter-assay coefficients of variation (CVs) were 6.3 and 9.3%, respectively. Dehydroepiandrosterone sulfate (DHEAS) was assayed automatically by immunochemiluminescence (Immulite assay, DPC, Madrid, Spain). Intra- and inter-assay CVs were 5.6 and 10.1%, respectively. Cortisol was measured by immunochemiluminescence (Cortisol ELISA assay, DSL). Intra- and inter-assay CVs were 2.4 and 6.1%, respectively.

Calculations and analyses

Ponderal index at birth was calculated as (weight/length3) in 657 subjects who had birth length measured. Body mass index (BMI) at age 8 yr was calculated as (weight/height2) in all 770 subjects. Body weight, BMI, and waist circumference at 8 yr 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 as change in body weight SD score between birth and 3 yr; a gain in weight SD score greater than 0.67 was taken to indicate clinically significant "catch-up" weight gain, as 0.67 SD represents the width of each centile band on standard growth charts (i.e. 2nd to 9th, 9th to 25th, 25th to 50th centiles, etc.). Similarly, a decrease in weight SD score between 0 and 3 yr by more than 0.67 indicated "catch-down" weight gain (7).

Sex differences were examined by t tests. Univariable and multivariable determinants of DHEAS, androstenedione, and cortisol levels were examined by linear regression analysis. Hormone levels showed positively skewed distributions and were log-transformed to normal distributions. However, untransformed values gave essentially identical correlations and P values, and these are presented for ease of interpretation. Results are displayed as regression coefficients (B) ± 95% CI, which indicate the predicted degree of change in hormone levels (units) for a 1 SD score change in body size.

Cortisol levels decreased with later time of day at blood sampling (–21.6 nmol/liter·h; P < 0.001), and this was allowed for in subsequent analyses. Androstenedione (P = 0.9) and DHEAS (P = 0.9) levels did not vary with time of day.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Hormone levels and body size at 8 yr are displayed by sex in Table 1Go. Boys were taller but thinner than girls and had lower levels of androstenedione, but there were no differences in DHEAS or cortisol levels.


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  		TABLE 1. Body size and adrenal hormone levels at age 8 yr, by sex

 
In univariate analyses, adjusted for sex, time of blood sampling, and gestational age, androstenedione and DHEAS levels at age 8 yr, but not cortisol levels, were inversely related to birth weight and birth length (Table 2Go); DHEAS levels were also inversely related to ponderal index at birth. In each sex, the correlations between lower birth weight and higher adrenal androgen levels were significant and showed similar effect sizes (DHEAS in boys: B = –2.5 µg/dl/SD; 95% CI, –4.7 to –0.2; P = 0.03; DHEAS in girls: B = –3.8 µg/dl/SD; 95% CI, –6.2 to –1.4; P = 0.002; Fig. 1Go; androstenedione in boys: B = –0.15 nmol/liter/SD; 95% CI, –0.25 to –0.06; P = 0.002; androstenedione in girls: B = –0.13 nmol/liter/SD, 95% CI, –0.24 to –0.02; P = 0.02). Androstenedione and DHEAS levels, but not cortisol levels, were also positively related to current body size (Table 2Go).


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  		TABLE 2. Univariable regression coefficients (95% CI) between hormone levels at 8 yr and SD scores (SDS) for body size at birth and at age 8 yr

 


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  		FIG. 1. Inverse relationship between birth weight and DHEAS levels at 8 yr in both boys (gray columns, P trend = 0.03) and girls (white columns, P trend = 0.02). Unadjusted geometric means +1 SEM range.

 
In multivariable regression analyses, both lower birth weight and larger current body weight independently predicted higher adrenal androgen levels (Table 3Go, Fig. 2Go). Furthermore, children who showed rapid postnatal weight gain between 0–3 yr had higher adrenal androgen levels at age 8 yr, even after allowing for current body weight (androstenedione, P = 0.004; DHEAS, P = 0.002; Fig. 3Go), but no differences in cortisol levels (P = 0.2).


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  		TABLE 3. Multivariable regression coefficients (95% CI) between hormone levels at 8 yr and SD scores (SDS) for birth weight and weight at 8 yr

 


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  		FIG. 2. DHEAS levels at age 8 yr, by tertiles of birth weight and weight at 8 yr. Geometric means.

 


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  		FIG. 3. Change in weight SD score between birth and 3 yr predicts androstenedione and DHEAS levels at age 8 yr (P trend, adjusted for weight at 8 yr; androstenedione, P = 0.004; DHEAS, P = 0.002). Geometric means +1 SD range.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Case-control studies in Barcelona-Spanish populations have described that females born small for gestational age but with normal childhood size may be predisposed to exaggerated adrenarche and its clinical manifestation, precocious pubarche (3, 4). A further study of discordant birth weight siblings showed that the small for gestational age sibling had higher DHEAS levels at age 8 yr only if subsequent catch-up weight had occurred (8), and, in a longitudinal childhood study, the rise in adrenal androgen levels coincided with rapid gains in BMI (9). Our current study, in a large population-based sample of children, shows that the relationship between lower birth weight and higher adrenal androgen levels in childhood is continuous throughout the range of normal birth weights, and that the effect size is similar in males and females. Adrenal androgen levels were highest in those small infants who become heavier than average during early childhood, a growth pattern that is characteristically seen after in utero growth restraint (10).

Clinical evaluation of pubarche was unavailable in our cohort but is likely to be rare in this largely white United Kingdom cohort. Levels of DHEAS during adrenarche are usually above 40–50 µg/dl (11). However, the manifestation of clinical symptoms may also depend on genetic differences in androgen receptor sensitivity, and white United Kingdom subjects may be less sensitive than Barcelona-Spanish subjects (12).

The adrenal androgens, dehydroepiandrosterone and DHEAS, emanate chiefly from the zona reticularis (13), and plasma DHEAS levels can be used to assess adrenal androgen production rates (14). The zona reticularis is the morphological equivalent of the fetal zone of the adrenal cortex. The fetal zone disappears in the first few months after birth, and production of DHEA and DHEAS virtually ceases, only resuming around 6 yr later at adrenarche (15, 16). Low-birth-weight infants have hypoplasia of the fetal zone at birth (17), with lower plasma and urine DHEAS levels in the first 24 h of life compared with normal-birth-weight infants (18, 19). Our findings together with previous case control studies (3, 4, 10) strongly indicate that postnatal adrenal androgen secretion may be programmed during fetal and early postnatal development. Palmert et al. (20) have suggested that adrenal androgen production follows an exponential curve in each individual, increasing gradually from early childhood, and thus adrenarche might be set in early childhood; however, those results were obtained in girls who had first experienced precocious puberty and were subsequently under LHRH-agonist treatment.

The regulation of adrenarche is still unclear. It has been suggested that increased IGF-I or insulin activity stimulates serine phosphorylation of P450c17, which by increasing 17,20-lyase activity promotes adrenal androgen production and could stimulate adrenarche (21). Case control studies have reported that IGF-I and insulin levels are higher in girls (22, 23) and boys (24) with premature adrenarche than in control children. In these ALSPAC children, the combination of low birth weight and rapid weight gain in early postnatal life predicts increased total and central adiposity at age 5 yr (7), higher IGF-I levels at age 5 yr (25), and lower insulin sensitivity at age 8 yr (26). Thus, increased IGF-I and insulin levels after low birth weight and rapid infancy growth could lead to the development of higher adrenal androgen production and to earlier or more pronounced adrenarche.

In contrast to adrenal androgen levels, we found no association between circulating cortisol levels and size at birth or postnatal weight gain. It has been suggested that programming of higher cortisol secretion and activity could be a further mechanism that explains the association between low birth weight and adult disease risk, by resulting in insulin resistance, central obesity, and elevated blood pressure (2). Fetal exposure to glucocorticoids retards fetal growth (27) and in animals can permanently alter cortisol secretion and result in increased blood pressure in later life (28, 29). In adult humans, early-morning fasting cortisol levels and ACTH-stimulated cortisol levels have been reported to rise with lower birth weight (30, 31). In a small study of children in Salisbury, United Kingdom, a quadratic or u-shaped relationship between birth weight and total urinary cortisol metabolites was observed (32). As performed in our study, a single blood measurement gives a poor assessment of adrenal function because cortisol secretion is pulsatile with three to four peaks of increasing amplitude occurring overnight, and the last and highest plasma levels can occur anytime between 0600 and 1000 h (33). Thus, our observations do not exclude the possibility that variations in cortisol secretion or activity may also contribute to birth weight and adult disease associations. Timed urine samples would provide a better estimation of cortisol production (33) and could also be used to estimate activity of the 11-ß-hydroxysteroid dehydrogenases, which regulate cortisol activity (34).

Adrenal androgen secretion has been postulated to trigger the activation of puberty (35). Thus, our findings might indicate that reported links between rapid infancy growth and earlier onset of puberty (36, 37) could be mediated by increased adrenal androgen levels. However, in some studies, premature adrenarche alone causes only a transient acceleration in growth and bone maturation with negligible effects on the onset and progression of puberty and on final height (38, 39). Further follow-up of these children through puberty is planned and will help to clarify the relationship between birth weight, androgen levels, age at onset, and rate of progression of puberty.

Precocious pubarche in girls has been associated with the subsequent development of ovarian hyperandrogenism, central obesity, hyperlipidemia, and insulin resistance during postpuberty, particularly in those subjects with history of low birth weight (3, 5). Low birth weight and rapid postnatal growth predict increased risk for adult type 2 diabetes and cardiovascular disease (40, 41), and a number of endocrine-metabolic mechanisms have been proposed to explain this link: in particular, the development of insulin resistance (42). Our current results show that this early growth pattern predicts increased adrenal androgen levels, and we suggest that the development of higher adrenal androgen secretion could further contribute to these links between early growth rates and later disease risks, possibly by enhancing insulin resistance and central fat deposition (43, 44).

In conclusion, the relationship between lower birth weight and higher adrenal androgen levels in childhood is continuous throughout the range of normal birth weights and shows no sex differences. Longer-term follow-up of the cohort will allow exploration of the influence of higher adrenal androgen levels on the age at onset and progression of puberty and body composition changes.


   Acknowledgments
 
We are extremely grateful to all the children and parents who took part and to the midwives for their cooperation and help in recruitment. The ALSPAC study team includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.


   Footnotes
 
This work would not have been undertaken without the financial support of the Medical Research Council, the Wellcome Trust, the United Kingdom Department of Health, the Department of the Environment, the Department for Education and Employment, the National Institutes of Health, and a variety of medical research charities and commercial companies. ALSPAC is part of the World Health Organization-initiated European Longitudinal Study of Parents and Children. K.O. was supported by a Medical Research Council Clinical Training Fellowship. D.D. is supported by the Wellcome Trust and the Juvenile Diabetes Research Foundation. L.I. was supported by a Visiting Fellowship from the European Society for Pediatric Endocrinology. F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research, Flanders, Belgium.

Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; B, regression coefficient; BMI, body mass index; CI, confidence interval; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate.

Received October 23, 2003.

Accepted January 23, 2004.


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 Introduction
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 Results
 Discussion
 References
 

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Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society
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D. M. Sloboda, R. Hart, D. A. Doherty, C. E. Pennell, and M. Hickey
Age at Menarche: Influences of Prenatal and Postnatal Growth
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N. Karaolis-Danckert, A. E Buyken, K. Bolzenius, C. Perim de Faria, M. J Lentze, and A. Kroke
Rapid growth among term children whose birth weight was appropriate for gestational age has a longer lasting effect on body fat percentage than on body mass index
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E. KAJANTIE
Fetal Origins of Stress-Related Adult Disease
Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 11 - 27.
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C. S. Tam, F. de Zegher, S. P. Garnett, L. A. Baur, and C. T. Cowell
Opposing Influences of Prenatal and Postnatal Growth on the Timing of Menarche
J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4369 - 4373.
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M. I. Hernandez, A. Martinez, T. Capurro, V. Pena, L. Trejo, A. Avila, T. Salazar, S. Asenjo, G. Iniguez, and V. Mericq
Comparison of Clinical, Ultrasonographic, and Biochemical Differences at the Beginning of Puberty in Healthy Girls Born Either Small for Gestational Age or Appropriate for Gestational Age: Preliminary Results
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3377 - 3381.
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G. Teilmann, C. B. Pedersen, N. E. Skakkebaek, and T. K. Jensen
Increased Risk of Precocious Puberty in Internationally Adopted Children in Denmark
Pediatrics, August 1, 2006; 118(2): e391 - e399.
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L. Ibanez, R. Jimenez, and F. de Zegher
Early Puberty-Menarche After Precocious Pubarche: Relation to Prenatal Growth
Pediatrics, January 1, 2006; 117(1): 117 - 121.
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L. Ibanez, A. Fucci, C. Valls, K. Ong, D. Dunger, and F. de Zegher
Neutrophil Count in Small-for-Gestational Age Children: Contrasting Effects of Metformin and Growth Hormone Therapy
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