This Article Abstract Full Text (PDF) All Versions of this Article: 90/5/2781    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hng, T.-M. Articles by McLean, M. Search for Related Content PubMed PubMed Citation Articles by Hng, T.-M. Articles by McLean, M. Related Collections Adrenal and Hypertension Neuroendocrinology and Pituitary Pediatric Endocrinology

Growth Hormone and Cortisol Dynamic Function in Relation to Birth Weight: A Study in Adult Twins

Centre for Diabetes and Endocrinology Research, Westmead Hospital, Westmead NSW 2145, Australia

Address all correspondence and requests for reprints to: Mark McLean, Centre for Diabetes and Endocrinology Research, Westmead Hospital, Westmead NSW 2145, Australia.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Low birth weight (BW) is associated with an increased risk of the metabolic syndrome and cardiovascular disease in adulthood. Programmed hypersecretion of glucocorticoids or reduced secretion of GH has been postulated as mechanisms for this effect. However, other variables such as premature birth may confound the association of birth size with later endocrine function. To separate the effect of BW from other variables, we examined basal and dynamic function of the hypothalamus-pituitary-adrenal axis and GH-IGF axis in twin siblings with differing BW. Twenty pairs of same-sex healthy adult twins underwent measurement of serum cortisol before and after low-dose (1 µg) Synacthen stimulation, and plasma GH during glucose suppression and exercise stimulation. In paired statistical analysis, the lower BW twins had significantly lower morning serum cortisol than their heavier BW siblings (mean intrapair difference 60 nmol/liter, 95% confidence interval 5–114, P < 0.03) but no difference in peak cortisol level after ACTH. Lower BW was associated with a trend to lower baseline plasma GH and a significantly lower peak GH concentration after exercise (difference 7.6 mU/liter, 95% confidence interval 1.7–13.5, P = 0.01). Intrapair differences in basal and stimulated cortisol and basal GH also correlated significantly with the intrapair difference in BW, demonstrating a dose-response effect of BW on hypothalamus-pituitary-adrenal axis function and basal GH secretion. In a twin model that isolates BW from other confounding variables, our data suggest that low BW programs individuals for reduced GH secretion and reduced basal cortisol secretion but preservation of a cortisol secretory response to ACTH.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
EPIDEMIOLOGICAL STUDIES HAVE shown that low weight at birth is associated with an increased risk of cardiovascular disease, hypertension, type 2 diabetes, and the metabolic syndrome in adulthood (1, 2, 3, 4, 5). The fetal programming hypothesis proposed by Barker (6) postulates that stress in fetal life, e.g. undernutrition or placental insufficiency, provokes adaptive changes in endocrine and metabolic systems that then become permanently programmed as part of the individual’s phenotype. Although these adaptations may improve the chance of survival to birth, their persistence into postnatal life might later predispose to adult diseases.

It seems logical to implicate growth-promoting and stress-responsive hormone systems as possible mechanisms for fetal programming of adult diseases. It is notable that in adult life the phenotypes of GH deficiency or glucocorticoid excess both have significant overlap with aspects of the metabolic syndrome (central adiposity, insulin resistance, hypertension, and dyslipidemia). In animals stressful intrauterine events, e.g. maternal undernutrition, are associated with growth restriction and increased fetal cortisol secretion, with persisting overactivity of the hypothalamic-pituitary-adrenal (HPA) axis in adult offspring (7). Children born small for gestational age have increased circulating levels of glucocorticoids and CRH (8), and reduced GH and IGF levels (9). It is less clear whether these hormonal effects persist into later life in humans. Some studies have found reduced GH secretion in individuals with low birth weight, compared with normal birth weight controls, whereas other case-control studies have found no effect (10). Studies of HPA axis function after fetal growth restriction have also been inconsistent. Low birth weight (BW) has been associated with elevated morning plasma cortisol levels in one cohort study (11) and increased cortisol responsiveness to stimulation with synthetic ACTH in another (12). Conversely, other population studies have found no association between BW and unstimulated serum cortisol concentrations in childhood (13), middle age (14), or the elderly (15).

These birth cohort studies are all subject to significant confounding by genetic, gestational, and environmental variables. In particular, premature birth might produce programming effects that are independent of size at birth; and cohort studies based on historical birth records are unable to determine whether an individual’s low BW is appropriate or small for their gestation. One means of controlling for such confounding is the use of twin studies. In a pair of twin infants, one is invariably of greater BW than the other, and a considerable disparity in size at birth may occur if placental transport of oxygen and nutrients favors one twin over the other. Genetic differences are eliminated in studies of monozygotic twins, and even with dizygotic twins these effects are greatly reduced. Both subjects are the same age, are born at the same gestational age, and have matched early social and environmental experiences. Recently studies in twin pairs demonstrated higher blood pressure (16) and increased risk of type 2 diabetes (17, 18) in the sibling with lowest BW. In this study we used a twin model to investigate the effect of BW on dynamic function of the HPA axis and GH-IGF axis in adult life. We postulated that within a twin pair, the sibling of lower BW would have relative up-regulation of the HPA axis and relative down-regulation of the GH-IGF axis in response to dynamic testing, compared with his/her sibling. Furthermore, we expected that the extent of intrapair difference in hormone function would correlate with the difference in BW.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Recruitment of twin pairs

Twenty sets of healthy, adult, same-sex twins were recruited through the database of the Australian Twin Registry. Copies of the original birth records were obtained before the commencement of the study to verify birth weight. Investigators involved in the clinical measurements were blinded to the information contained in the birth records. Zygosity was assigned by report of the twins themselves, and no genetic determination of zygosity was performed.

Dynamic hormonal studies

Twin siblings underwent testing together on the same day. At 0730 h a venous cannula was placed for sampling and drug administration. Samples were obtained at 0800 h for measurements of fasting plasma GH, IGF-1, and serum cortisol. A 75-g oral glucose load was administered to suppress GH secretion to a low baseline. Two hours after glucose loading, samples were obtained for repeat plasma GH and serum cortisol measurements and 1 µg of synthetic ACTH 1–24 (Synacthen; Novartis Pharmaceuticals, Sydney, Australia) was administered iv. A test for exercise stimulation of GH secretion was timed to coincide with the cortisol stimulation test. After a short warm-up period, subjects undertook 60 sec of intense exercise using a bicycle ergometer. The aim of the exercise stimulation was to reach the subject’s maximal exercise capacity by the end of 1 min. Graded increments in resistance on the ergometer were made every 10 sec, ensuring a significant exercise stress, regardless of fitness level. Serum lactate levels were measured immediately after exercise. Serum cortisol and plasma GH were measured 30 min after stimulation.

Laboratory methods

Plasma GH, IGF-1, and serum cortisol were assayed in duplicate (twin pairs batched together) using a solid-phase, two-site chemiluminescent immunometric assay (Immulite; Diagnostic Products Corp., Flanders, NJ). The interassay coefficient of variation (CV) for the GH assay is 5% at the level of 7.6 ± 0.4 mU/liter and the minimum detectable level was 0.026 mU/liter. The interassay CV for the cortisol assay is 7% at the level of 577 ± 4.0 nmol/liter with a minimum detectable level of 5.5 nmol/liter. The interassay CV for the IGF-I assay is 6.6% (all data from manufacturers). Serum lactate was measured with a COBAS Integra 800 analyzer (Roche, Basel, Switzerland) using an enzymatic calorimetric method (lactate oxidase and 4-aminoantipyrine).

Statistical analysis

Intrapair differences in outcome measures are calculated by subtracting the value of the lighter BW twin from the heavier BW twin in each pair. Consequently, positive results indicate that a greater value was found in the higher BW twin of each pair, whereas a negative value indicates higher values occurred in the lower BW sibling. These are reported as mean and 95% confidence interval (CI). Paired t tests were used to analyze within-pair differences. Intrapair differences in outcome measures were correlated with BW difference using the Pearson correlation coefficient. Two-tailed tests were used for all statistical analyses and P 0.05 was accepted as statistically significant. Statistical analysis was performed with the SPSS for Windows statistical package (version 11.5; SPSS Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Birth details and adult anthropometry

The characteristics of the participants are described in Table 1. There was a preponderance of females among the volunteer subjects. Mean BW difference between twin siblings was 298 g with a range of 35–907 g. There were no subjects with a known endocrine disorder. When comparisons were made between twin siblings, the twin lightest at birth had significantly higher diastolic blood pressure (intrapair difference 4.3 mm Hg, 95% CI 1.7 to 7.7, P = 0.02) and a trend toward higher systolic blood pressure (intrapair difference 4.5 mm Hg, 95% CI –0.1 to 9.1, P = 0.055), compared with their sibling. In monozygotic twin pairs, the twin heaviest at birth was significantly taller as an adult (intrapair difference 0.7 cm, 95% CI 0.05–1.39, P = 0.04). There was no significant difference in height between dizygotic twins; and no intrapair difference in adult weight or body mass index in any subject groups.

Baseline serum cortisol in the 40 subjects varied from 119 to 485 nmol/liter (43–176 ng/ml). Intrapair differences in hormonal data are shown in Fig. 1. Baseline serum cortisol concentrations were significantly higher in the heavier BW twin with a mean intrapair difference of 60 nmol/liter (22 ng/ml) (95% CI 5–114 nmol/liter, P < 0.03). All subjects demonstrated a rise in serum cortisol concentration after synthetic ACTH administration. When expressed as a percentage of the baseline cortisol concentration, the incremental rise after ACTH varied from 37 to 413%. The cortisol response was significantly greater in the lower BW twin [intrapair difference –63 nmol/liter (–23 ng/ml) (95% CI –1 to–124 nmol/liter, P = 0.05]. In these subjects the greater cortisol increment compensated for the lower baseline concentration, so the poststimulation cortisol concentration did not differ between twin siblings (data not shown).

View larger version (9K): [in this window] [in a new window]   FIG. 1. Forest plot showing the 95% CI for the mean of intrapair difference between twin siblings. The notches on the baseline represent 2 cm for height, 2 mU/liter (5.2 ng/ml) for all indices of GH, 2 nmol/liter (15.3 ng/ml) for IGF-I, and 100 nmol/liter (36.2 ng/ml) for all indices of cortisol.

Fasting plasma GH in the 40 subjects varied from 0 to 38.6 mU/liter (0–15 ng/ml), but 120 min after glucose loading, GH levels were suppressed to a mean of 1.0 mU/liter (0.38 ng/ml) and did not differ significantly between twin siblings. The fasting GH concentration tended to be higher in the heavier BW twin, but this difference fell short of statistical significance [intrapair difference 3.5 mU/liter (1.35 ng/ml), 95% CI –0.7 to 7.7 mU/liter, P = 0.10]. At the conclusion of the exercise stimulation, serum lactate levels were measured to assess the extent of metabolic stress achieved. Elevated serum lactate levels occurred after exercise in all subjects [mean 6.1 mmol/liter (55 mg/dl), range 2.5–10.8 mmol/liter; the laboratory normal range for resting individuals is 0.63–2.44 mmol/liter (5.7–22.0 mg/dl)]. There was no difference in lactate levels between twin siblings (data not shown). Plasma GH rose after exercise in all but one subject [mean rise 10.5 mU/liter (4.0 ng/ml), range 0–39.1 mU/liter]. The intrapair differences in fasting plasma GH, IGF-I, and plasma GH response to exercise are shown in Fig. 1. After exercise the heavier BW twin had a significantly higher peak GH concentration [intrapair difference 7.6 mU/liter (2.9 ng/ml), 95% CI 1.7–13.5 mU/liter, P = 0.01] and a greater incremental GH response to exercise [intrapair difference 8.7 mU/liter (3.3 ng/ml), 95% CI 2.8–14.7 mU/liter, P = 0.006], compared with the lower BW sibling. There was no difference in plasma IGF-I between siblings.

Hormonal differences vs. BW difference

Because the intrapair difference in BW varied across a wide range (35–907 g), we determined whether the twins with the greatest disparity in BW also had the greatest differences in adult hormonal function (Fig. 2). There was a significant positive correlation between intrapair BW difference and intrapair difference in fasting cortisol (r = 0.60, P = 0.005), prestimulation cortisol (r = 0.46, P = 0.04), and fasting GH (r = 0.51, P = 0.02). There was a significant negative correlation between BW difference and difference in percentage cortisol increment after ACTH (r = 0.47, P = 0.04) but no significant association of BW difference with difference in poststimulation cortisol or GH levels, GH incremental response, or serum IGF-I.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Correlation of intrapair BW difference and difference in basal and dynamic hormonal measures. To convert GH milliunits per liter to nanograms per milliliter, multiply by 2.6. To convert cortisol nanomoles per liter to nanograms per milliliter, divide by 2.759.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Animal studies have shown that stress during fetal life programs offspring for overactivity of the HPA axis (7, 21). Cohort studies in humans have sought correlations between size at birth and activity of the HPA axis in adult life. BW was inversely associated with excretion of urinary cortisol metabolites in a study of 9-yr-old children (22) and morning serum cortisol in adults (11). However, conflicting findings have been reported from other cohorts. A study of more than 400 Finnish adults aged 65–75 yr found no consistent association between BW and serum cortisol concentration in men or women (23), and a study of frequently sampled 24-h serum cortisol profiles in elderly men and women found no relationship of any parameter of cortisol secretion to BW (14). Such cohort studies are subject to important confounding effects such as genetic and socioeconomic influences, maternal size, unrecognized prematurity, and survivor bias. Prematurity is a particularly problematic issue because the historical birth records on which these studies are based cannot differentiate low BW individuals who were subjected to fetal growth restriction from those born preterm with appropriate size for gestation. Two small studies have reported that prematurity has a significant effect on programming of the HPA axis, which is independent of size at birth (13, 24). Furthermore, in the Finnish birth cohort for which estimates of gestational age at birth were available, there seemed to be differing relationships between adult cortisol levels and BW for the individuals born before 40 wk gestation (inverse correlation) and those born after 40 wk (positive correlation) (23). This suggests that premature birth and fetal growth restriction have separate and opposing programming effects on the HPA axis. A recent study also demonstrated that premature birth is associated with insulin resistance in prepubertal children, and this effect is independent of birth size (25).

Twin siblings are born at the same gestation but are often disparate for birth size. Examination of twins therefore provides an opportunity to separate the biological effect of birth size from the confounding effect of prematurity and other variables that might influence adult phenotype. A further advantage of twin studies is the ability to use a paired statistical analysis that has considerably more power than can be obtained from analysis of cohort data. Here we report the first study to use a twin model to explore the association between size at birth and adult function of the GH-IGF and HPA axes. We found that within healthy adult twin pairs, the sibling who was smallest at birth has a significantly lower basal serum cortisol level than the heavier BW sibling. However, in response to stimulation with ACTH, both twins achieve similar peak cortisol concentrations. This suggests that, when prematurity is controlled for, low BW is associated with reduced basal cortisol secretion but preservation of an adequate stress response. This finding was contrary to our a priori hypothesis and is inconsistent with the hormonal programming theory invoking chronic hypercortisolism as a contributor to the pathogenesis of the metabolic syndrome in low BW humans. Although this may be a type 1 error in our study due to relatively small sample size, this seems unlikely, given that there was also a positive relationship between intrapair fasting cortisol difference and intrapair BW difference. More likely, the association between lower BW and lower basal cortisol is a true effect, which we have recognized because the twin model better accounts for the confounding effect of prematurity. Our observation of an increased dynamic cortisol response to ACTH stimulation in the low BW sibling is in agreement with a cohort study of men aged 66–77 yr, which found that lower BW was associated with increased cortisol responsiveness to ACTH but no change in plasma cortisol after dexamethasone (12). However, because baseline cortisol levels were lower, the greater increment in plasma cortisol in the lower BW twins resulted in similar, rather than higher, absolute levels of cortisol, compared with their higher BW sibling.

We found a trend to lower baseline GH concentrations, and shorter adult stature among monozygotic twins, in the twin with lowest BW. Lower BW twins also had a significantly lower GH response to stimulation. Function of the GH-IGF axis in relation to size at birth has been assessed by others; again with conflicting results (9). In normal children there is an inverse relationship of BW and plasma IGF-I (26), but this is confounded by effects of current size and growth rate. In a cohort of young adults in Adelaide, South Australia, low BW was found to be associated with reduced urinary GH excretion (27). In contrast, in a small British study in which plasma GH was measured every 20 min for 24 h, there was no correlation of peak GH or median GH with BW (28). In a study of 40 healthy 18- to 25-yr-old women, serum IGF-I was inversely associated with BW, whereas current weight was positively associated with IGF-I (29). By contrast, no association was found between BW and serum IGF-I in the Adelaide cohort (9) or a British study (10). Interpretation of these data is made difficult by the complicated relationships among GH, IGF-I, and the IGF binding proteins. Some data also suggest relative GH resistance in association with low BW (9), and this may explain why alterations in GH levels are not invariably associated with parallel changes in IGF-I, as we have again observed.

Importantly, we observed that the greatest differences in basal GH and cortisol levels, and in dynamic cortisol responses, occurred in the twin pairs with greatest disparity in BW, whereas pairs closely matched for BW shared very similar adult hormone function. This is evidence of a dose-response effect of birth size on circulating cortisol and GH concentrations in adulthood. These data are consistent with life-long remodeling of endocrine function in response to intrauterine experience. Although the variations in hormone function that we observed were within population normal ranges, the finding of significant differences in adult phenotype (height, blood pressure) suggests that these are biologically significant effects. A number of limitations of the present study need to be acknowledged. There was a marked preponderance of female twin pairs among volunteers for the study, and this limits the extent to which results can be generalized to males, although the previous cohort studies discussed above suggest similar outcomes of hormonal programming for both genders. Zygosity was not formally determined in the current study, but similar trends were seen when the monozygotic and dizygotic groups are considered separately, suggesting that reallocation of zygosity for some pairs would not affect the overall results. The sample size of 20 twin pairs (40 individuals) is small, but conversely, the ability to perform paired statistical analysis greatly enhances the power of the study. We chose to use low-dose (1 µg) ACTH 1–24 and a brief exercise challenge as stimulators of dynamic hormone responses because of their similarity to everyday physiological stimulation of cortisol and GH secretion.

Our findings in a useful twin model suggest that smaller size at birth is associated with lifelong down-regulation of GH secretion and a significant reduction in basal serum cortisol concentration, but preservation of the cortisol response to ACTH stimulation in adult life. An important contribution of this study is the ability of the twin model to separate the effect of gestation at birth from that of birth weight. The effect of low BW on HPA axis function seems to be opposite that of premature birth, possibly explaining the conflicting results of earlier cohort studies, which were unable to separate these two variables. These phenomena are likely to represent long-term programmed hormonal adaptations initiated by conditioning events in fetal life. Better understanding of the pathophysiology of fetal adaptation will permit important insights into disease prevention and management.

	Footnotes

 
This work was supported by the National Health and Medical Research Council of Australia and the Australian Twin Registry.

First Published Online March 1, 2005

Abbreviations: BW, Birth weight; CV, coefficient of variation; HPA, hypothalamic-pituitary-adrenal.

Received December 20, 2004.

Accepted February 18, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ 1989 Weight in infancy and death from ischaemic heart disease. Lancet 2:577–580[Medline]
2. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD 1991 Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303:1019–1022
3. Barker DJ, Bull AR, Osmond C, Simmonds SJ 1990 Fetal and placental size and risk of hypertension in adult life. BMJ 301:259–262
4. Barker DJ 1999 The fetal origins of type 2 diabetes mellitus. Ann Intern Med 130:322–324[Free Full Text]
5. Phillips DI 1998 Birth weight and the future development of diabetes. A review of the evidence. Diabetes Care 21(Suppl 2):B150–B155
6. Barker DJ 1994 Mothers, babies and disease in later life. London: BMJ Publishing
7. Matthews SG 2002 Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 13:373–380[CrossRef][Medline]
8. Giles WB, McLean M, Davies JJ, Smith R 1996 Abnormal umbilical artery doppler waveforms and cord blood corticotropin-releasing hormone. Obstet Gynecol 87:107–111[Abstract]
9. Holt RI 2002 Fetal programming of the growth hormone-insulin-like growth factor axis. Trends Endocrinol Metab 13:392–397[CrossRef][Medline]
10. Holt RI, Syddall HE, Phillips DI, Martyn CN, Gluckman PD, Breier BH, Wood PJ, Fall CH 2004 Serum insulin-like growth factor-I concentrations in late middle age: no association with birth weight in three U.K. cohorts. Acta Physiol Scand 180:359–366[CrossRef][Medline]
11. Phillips DI, Barker DJ, Fall CH, Seckl JR, Whorwood CB, Wood PJ, Walker BR 1998 Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 83:757–760[Abstract/Free Full Text]
12. Reynolds RM, Walker BR, Syddall HE, Andrew R, Wood PJ, Whorwood CB, Phillips DI 2001 Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 86:245–250[Abstract/Free Full Text]
13. Tenhola S, Martikainen A, Rahiala E, Parviainen M, Halonen P, Voutilainen R 2002 Increased adrenocortical and adrenomedullary hormonal activity in 12-year-old children born small for gestational age. J Pediatr 141:477–482[CrossRef][Medline]
14. Fall CH, Dennison E, Cooper C, Pringle J, Kellingray SD, Hindmarsh P 2002 Does birth weight predict adult serum cortisol concentrations? Twenty-four-hour profiles in the United kingdom 1920–1930 Hertfordshire Birth Cohort. J Clin Endocrinol Metab 87:2001–2007[Abstract/Free Full Text]
15. Kajantie E, Eriksson J, Osmond C, Wood PJ, Forsen T, Barker DJ, Phillips DI 2004 Size at birth, the metabolic syndrome and 24-h salivary cortisol profile. Clin Endocrinol (Oxf) 60:201–207[CrossRef][Medline]
16. Poulter NR, Chang CL, MacGregor AJ, Sneider H, Spector TD 1999 Association between birth weight and adult blood pressure in twins: historical cohort study. BMJ 319:1330–1333[Abstract/Free Full Text]
17. Poulsen P, Vaag AA, Kyvik KO, Jensen DM, Beck-Nielsen H 1997 Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetologia 40:439–446[CrossRef][Medline]
18. Iliadou A, Cnattingius S, Lichtenstein P 2004 Low birth weight and type 2 diabetes: a study on 11,162 Swedish twins. Int J Epidemiol 33:948–953[Abstract/Free Full Text]
19. Wilson J 1999 The Barker hypothesis—an analysis. Aust NZ J Obstet Gynaecol 39:1–7[Medline]
20. Phillips D 2002 Endocrine programming and fetal origins of adult disease. Trends Endocrinol Metab 13:363[CrossRef][Medline]
21. Weinstock M 2001 Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 65:427–451[CrossRef][Medline]
22. Clark PM, Hindmarsh PC, Shiell AW, Law CM, Honour JW, Barker DJ 1996 Size at birth and adrenocortical function in childhood. Clin Endocrinol (Oxf) 45:721–726[CrossRef][Medline]
23. Kajantie E, Phillips DI, Andersson S, Barker DJ, Dunkel L, Forsen T, Osmond C, Tuominen J, Wood PJ, Eriksson J 2002 Size at birth, gestational age and cortisol secretion in adult life: foetal programming of both hyper- and hypocortisolism? Clin Endocrinol (Oxf) 57:635–641[CrossRef][Medline]
24. Walker BR, Irving RJ, Andrew R, Belton NR 2002 Contrasting effects of intrauterine growth retardation and premature delivery on adult cortisol secretion and metabolism in man. Clin Endocrinol (Oxf) 57:351–355[CrossRef][Medline]
25. Hofman PL, Regan F, Jackson W, Jefferies C, Knight DB, Robinson EM, Cutfield WS 2004 Premature birth and later insulin resistance. N Engl J Med 351:2179–2186[Abstract/Free Full Text]
26. Fall CH, Pandit AN, Law CM, Yajnik CS, Clark PM, Breier B, Osmond C, Shiell AW, Gluckman PD, Barker DJ 1995 Size at birth and plasma insulin-like growth factor-1 concentrations. Arch Dis Child 73:287–293[Abstract]
27. Flanagan DE, Moore VM, Godsland IF, Cockington RA, Robinson JS, Phillips DI 1999 Reduced foetal growth and growth hormone secretion in adult life. Clin Endocrinol (Oxf) 50:735–740[CrossRef][Medline]
28. Fall C, Hindmarsh P, Dennison E, Kellingray S, Barker D, Cooper C 1998 Programming of growth hormone secretion and bone mineral density in elderly men: a hypothesis. J Clin Endocrinol Metab 83:135–139[Abstract/Free Full Text]
29. Jernstrom H, Olsson H 1998 Insulin-like growth factor-1 in relation to adult weight and birth weight in healthy nulliparous women. Int J Gynaecol Obstet 62:11–18[CrossRef][Medline]

This article has been cited by other articles:

				E. Kajantie, K. Feldt, K. Raikkonen, D. I. W. Phillips, C. Osmond, K. Heinonen, A.-K. Pesonen, S. Andersson, D. J. P. Barker, and J. G. Eriksson Body Size at Birth Predicts Hypothalamic-Pituitary-Adrenal Axis Response to Psychosocial Stress at Age 60 to 70 Years J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4094 - 4100. [Abstract] [Full Text] [PDF]

				J. Mairesse, J. Lesage, C. Breton, B. Breant, T. Hahn, M. Darnaudery, S. L. Dickson, J. Seckl, B. Blondeau, D. Vieau, et al. Maternal stress alters endocrine function of the feto-placental unit in rats Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1526 - E1533. [Abstract] [Full Text] [PDF]

				E. KAJANTIE Fetal Origins of Stress-Related Adult Disease Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 11 - 27. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 90/5/2781    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hng, T.-M. Articles by McLean, M. Search for Related Content PubMed PubMed Citation Articles by Hng, T.-M. Articles by McLean, M. Related Collections Adrenal and Hypertension Neuroendocrinology and Pituitary Pediatric Endocrinology