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Original Studies |
Medical Research Council Environmental Epidemiology Unit, University of Southampton (R.M.R., H.E.S., C.B.W., D.I.W.P.), S016 6YD Southampton, United Kingdom; Department of Medical Sciences, University of Edinburgh (R.M.R., R.A., B.R.W.), Western General Hospital, Edinburgh, Scotland EH4 2XU; and Regional Endocrine Unit, Southampton General Hospital (P.J.W.), S016 6YD Southampton, United Kingdom
Address all correspondence and requests for reprints to: Dr. R. M. Reynolds, Molecular Medicine Center, Western General Hospital, Edinburgh, Scotland EH4 2XU. E-mail: r.reynolds{at}ed.ac.uk
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recent observational studies have shown that low birth weight predicts subsequent hypertension, insulin resistance, glucose intolerance, and cardiovascular disease (11). Events in early life may have long-term effects on the HPAA. Exposure of pregnant rats to adverse influences during gestation, including undernutrition, treatment with dexamethasone, alcohol, physical restraint, or nonabortive maternal infections, results in the birth of small offspring with hypertension and insulin resistance. These animals also have elevated basal or stress-induced glucocorticoid secretion (12, 13, 14, 15). In studies of adult men, we recently reported that higher fasting morning plasma cortisol concentrations, a crude measure of cortisol secretion, are associated with higher blood pressure, plasma glucose and triglyceride concentrations, and lower birth weight (16, 17). Children and adolescents with lower birth weight have also been reported to excrete more cortisol or its metabolites in urine (18, 19). These studies have led to the hypothesis that events in early life permanently alter or program cortisol secretion, and that this together with increased obesity leads to a high prevalence of the metabolic syndrome and cardiovascular disease in adult life.
We investigated a group of men of known birth weight to test this hypothesis by characterizing abnormalities of cortisol secretion in relation to features of the metabolic syndrome, obesity, and birth weight.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We previously studied a cohort of 370 men born between 1920 and 1930 in East Hertfordshire, UK, for whom birth weights were recorded by midwives. In 1991, blood pressure was measured, and 75-g oral glucose tolerance tests were performed (20). In 1997 we approached the surviving 245 men, of whom 205 were suitable and agreed to take part in the present study. Subjects with clinical evidence of pituitary or adrenal disease and those who had received oral glucocorticoids in the previous 3 months were excluded. Subjects were invited to attend on any convenient day between July and December. Ethical committee approval and written informed consent were obtained.
Clinical protocol
At a preliminary interview, information about medical and social history, family history of diabetes and hypertension, smoking habits, alcohol consumption, and current medication was recorded, and subjects completed a 10-item General Health Questionnaire to measure mood (21). On another occasion, subjects ingested 0.25 mg dexamethasone at 2200 h and fasted overnight. The following morning they attended a local clinic at 0830 h, a 21-gauge butterfly cannula was inserted in an antecubital vein, and, after 30 min rest, a baseline blood sample was obtained before 1.0 µg freshly diluted ACTH-(1–24) (tetracosactrin, Synacthen, Alliance, Chippenham, UK) was injected as a bolus with a 10 mL saline flush. Venous blood was sampled through the cannula at 20, 30, 40, and 60 min after ACTH-(1–24) administration. Samples were centrifuged immediately, and plasma was stored at -80 C. Height and weight were recorded, and waist and hip circumferences were measured with steel tape at the level of the umbilicus and greater trochanter, respectively. Finally, subjects collected a 24-h urine sample at least a week before or a week after the dexamethasone/ACTH-(1–24) test.
Dexamethasone (0.25 mg) and ACTH-(1–24) (1 µg) doses were selected to provide an average 50–75% maximal suppression or stimulation, respectively, with a wide range (22, 23). More conventional doses [e.g. 1 mg dexamethasone or 250 µg ACTH-(1–24)] would be expected to produce maximal effects in all of these otherwise healthy participants and would not allow detection of subtle alterations in the control of cortisol secretion.
Laboratory methods
Measurements of glucose, triglyceride, and insulin
concentrations have been reported previously (20). RIAs
were used to measure plasma cortisol with Guildhay antisera
(24): corticosteroid-binding globulin (Medgenics
Diagnostics, Fleurus, Belgium), dehydroepiandrosterone
(Diagnostic Systems Laboratories, Inc., Webster, TX),
17
-hydroxyprogesterone (in-house RIA), progesterone (Immulite
analyzer, Diagnostic Products Ltd., Gwynedd,
Wales), and dexamethasone (enzyme-linked immunosorbent assay adapted
from Cozart Biosciences Ltd., Abingdon, UK). Urinary creatinine was
measured using the Jaffe reaction on the Bayer PLC
(Newbury, UK) Advia analyzer.
Cortisol, cortisone, and their metabolites were measured in urine by
gas chromatography/electron impact mass spectrometry (22, 25). Total cortisol metabolite excretion was calculated as
tetrahydrocortisols (THFs) plus tetrahydrocortisone (THE) plus cortols
plus cortolones. Ratios of urinary metabolites were used to infer
relative activation of the principle enzymes metabolizing cortisol.
Relative reduction by 5- and 5ß-reductases was inferred from the
5ß-THF/5-THF ratio. Whole body equilibrium between cortisol and
cortisone, determined by the balance of tissue-specific activities of
11ß-reductase and 11ß-dehydrogenase activities, was inferred from
the ratio of THFs/THE. Renal 11ß-dehydrogenase activity was inferred
from the urinary cortisol/cortisone ratio.
Statistical analysis
To obtain normally distributed variables, measurements of
glucose, triglycerides, urinary cortisol metabolites, peak cortisol
after ACTH-(1–24), and area under the curve after ACTH-(1–24)
administration for dehydroepiandrosterone and
17-hydroxyprogesterone, were loge transformed.
Geometric means and SDs are therefore presented for these
variables. Associations between continuously distributed variables were
assessed by the Pearson correlation coefficient, and associations
between continuous and categorical variables were assessed by the
Mann-Whitney U test or the two-sample t test as appropriate.
Multiple linear regression was then used to explore the relationship
between continuously distributed response variables and possible
explanatory variables, with adjustment for confounding factors.
Multiple logistic regression was used to analyze binary response
variables. In addition to analyzing the peak cortisol response to
ACTH-(1–24) using the methods described above, a longitudinal analysis
of the cortisol response to ACTH-(1–24) was also conducted. The
longitudinal approach considers the full series of cortisol data for
each subject and models the average response during the test in
relation to the factors of interest, taking into account the effects of
time and the autocorrelation of cortisol measurements within each
subject (26). All statistical analysis was carried out
using STATA, release 5; the xtgee feature was used to implement the
longitudinal analysis (Statacorp 1997, Stata Statistical software
release 5, Stata Corp., College Station, TX).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The men were aged between 66 and 77 (mean, 70.9; SD,
3.1) yr, with a mean body mass index (BMI) of 26.9 (SD,
3.7) kg/m2. Fifteen men had type 2 diabetes (2 h
glucose, 
11.1 mmol/L), and 33 had impaired glucose tolerance (IGT;
2-h glucose, 7.8–11.0 mmol/L). Mean systolic blood pressure was 161.5
mm Hg (SD, 22.1), and 73 men were receiving treatment with
antihypertensive drugs. Two subjects were excluded from analysis of
plasma cortisol concentrations because of extreme values; one had a
vaso-vagal event after iv cannulation, and the other was receiving
ethinylestradiol treatment. Six men had missing values for glucose
measurements. None of the measurements of cortisol in plasma or urine
correlated with age or differed in subjects receiving topical or
inhaled corticosteroid therapy (n = 16). None of the differences
in plasma cortisol described below were accounted for by variation in
plasma corticosteroid-binding globulin or dexamethasone concentrations
(data not shown).
Obesity, reflected in increased BMI, was associated with higher
blood pressure (r = 0.18; P = 0.04),
hypertriglyceridemia (r = 0.28; P = 0.0001), and
glucose intolerance (r = 0.16; P = 0.02). Obesity
was also associated with a linear increase in total urinary cortisol
metabolite excretion (r = 0.19; P = 0.006), but
did not predict plasma cortisol after dexamethasone or ACTH-(1–24)
administration. Central obesity, reflected in increased waist/hip ratio
(WHR), was associated with similar trends. In addition, increased WHR
predicted marginally lower plasma cortisol after 0.25 mg dexamethasone
(r = -0.13; P = 0.06) and disproportionately
higher excretion of 5- rather than 5ß-reduced metabolites of
cortisol (r = -0.14; P = 0.05). Obesity was not
associated with altered ratios of cortisol/cortisone metabolites.
Increased lean body mass, as judged by urinary creatinine excretion
(27), was also associated with higher total urinary
cortisol metabolites (r = 0.23; P = 0.001).
Neither obesity nor urinary creatinine was an independent predictor of
total urinary metabolite excretion in multiple regression analysis.
Urinary creatinine was not associated with plasma cortisol
concentration.
Men with a current or previous history of depression (n = 12) had greater peak plasma cortisol concentrations after ACTH-(1–24) [474.0 (SD, 1.1) vs. 428.7 (SD, 1.2) nmol/L; P = 0.03] and higher total urinary cortisol metabolites [median, 22.4 (interquartile range, 16.3–48.2) vs. 17.8 (11.3–24.8) mg/24 h; P = 0.04]. Men with manual occupations (class IIIM—V; n = 134) had no difference in plasma cortisol concentrations, but excreted less total cortisol metabolites than men with nonmanual occupations [class I—IIIN; n = 69; 15.9 (SD, 2.1) vs. 20.8 (SD, 1.8) mg/24 h; P = 0.008].
Associations with birth weight
Table 1
shows relationships between
birth weight and cortisol and its metabolites. A lower birth weight was
associated with a greater rise in plasma cortisol concentrations after
ACTH-(1–24) administration and a later peak time (Fig. 1), but no difference in plasma cortisol
after dexamethasone administration. The inverse relationship between
birth weight and adrenal ACTH-(1–24) responsiveness remained after
exclusion of men with IGT and type 2 diabetes and/or treated
hypertension and was not confounded by obesity. Differences in
adrenocortical responses to ACTH-(1–24) in a subgroup of men with
contrasting birth weight [>9.5 lb (4.31 kg) or 
6.5 lb (2.92 kg);
n = 12 in each group] were further explored by measurement of
other ACTH-dependent adrenal steroids in plasma. Men with lower birth
weight also had higher levels of dehydroepiandrosterone [mean area
under curve: birth weight, 6.5 lb, 6.5 (SD, 2.2)
nmol/L·h; >9.5 lb, 4.9 (SD, 1.5) nmol/L·h],
17-hydroxyprogesterone [birth weight, 6.5 lb, 9.7
(SD, 1.3) nmol/L·h; >9.5 lb, 8.1 (SD, 1.3)
nmol/L·h], and progesterone [birth weight 6.5 lb, 3.6
(SD, 0.5) nmol/L·h; >9.5 lb, 3.1 (SD, 0.7)
nmol/L·h], indicating that no common biosynthetic defect, such as
21-hydroxylase deficiency, accounts for the difference in cortisol
response.
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Associations with features of the metabolic syndrome
Table 2 shows relationships of
plasma cortisol and urinary cortisol metabolites to blood pressure,
glucose tolerance, and fasting plasma triglyceride concentrations after
correction for the potential confounding effects of obesity,
depression, social class, and urinary creatinine where appropriate.
Plasma cortisol concentration at 0900 h after dexamethasone
treatment was not associated with cardiovascular risk factors. However,
the peak plasma cortisol concentration after ACTH-(1–24) was higher in
men with higher blood pressure and higher fasting plasma triglyceride
concentrations and tended to be higher in men with higher post-glucose
plasma glucose concentrations. Likewise, in a longitudinal analysis of
the cortisol profiles, there were similar positive associations between
mean plasma cortisol concentration and these features, with or without
adjustment for potential confounding factors. In men with all three
features of the metabolic syndrome [previously defined
(28) as systolic blood pressure >160 mm Hg or subject
receiving antihypertensive therapy (n = 120), the presence of
impaired glucose tolerance or type 2 diabetes (n = 48), or fasting
plasma triglyceride >1.4 mmol/L; n = 101], peak and mean plasma
cortisol concentration over time were significantly elevated. Total
urinary cortisol metabolite excretion also tended to be greater in men
with these cardiovascular risk factors.
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Having examined individual features of the metabolic syndrome,
logistic regression modeling was then performed to identify predictors
of combined features of the metabolic syndrome (as defined above).
Potential variables included age, social class, birth weight, WHR, BMI,
plasma cortisol after dexamethasone, peak plasma cortisol after
ACTH-(1–24), total urinary cortisol metabolite excretion, and ratio of
5ß-/5-reduced metabolites of cortisol. The best fitting model
identified effects of BMI (P = 0.003), peak plasma
cortisol after ACTH-(1–24) (P = 0.03), and birth
weight (P = 0.02). The effect of birth weight was more
significant when peak plasma cortisol was excluded (P =
0.008), and the effect of peak plasma cortisol was more significant
when birth weight was excluded (P = 0.02). The
estimated odds ratios for the metabolic syndrome are 1.18 (95%
confidence interval, 1.06–1.32) for a unit increase in BMI, 1.55 (95%
confidence interval, 1.09–2.21) for a 1-lb decrease in birth weight,
and 1.28 (95% confidence interval, 1.02–1.61) for a 50 nmol/L
increase in peak cortisol concentration. The effects of WHR were
similar to those of BMI.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The explanation for activation of the HPAA in men with lower birth weight and features of the adult metabolic syndrome remains unclear. Rats exposed to glucocorticoids in utero have increased plasma glucocorticoid levels, which have been associated with lower levels of glucocorticoid receptors in brain and pituitary gland, which may impair negative feedback control of CRH and ACTH secretion (14). If the same programming of glucocorticoid receptor expression occurred in man, then suppression of plasma cortisol by dexamethasone would be expected to be impaired in men with lower birth weight, but we found that it was preserved. Indeed, as fasting plasma cortisol was higher in low birth weight men without dexamethasone (16, 17), but was not different after dexamethasone administration, the incremental effect of dexamethasone may be greater. However, dexamethasone may not cross the blood-brain barrier adequately at low doses in man (31), so this only tests the pituitary component of the negative feedback loop. Alternatively, elevated plasma cortisol may result from enhanced drive to CRH, ACTH, and cortisol secretion from higher centers manifest as an increase in plasma cortisol when stressed on first sampling. Or increased cortisol secretion could result from increased adrenocortical sensitivity to ACTH. Our measurements of other ACTH-dependent steroids exclude variance in cortisol response due to subclinical 21-hydroxylase deficiency (32). Other corticosteroid biosynthetic defects that have been proposed as being important in hypertension, such as 11ß-hydroxylase deficiency, predict lower, rather than higher, cortisol responses. Finally, the pattern of cortisol response to Synacthen in low birth weight subjects with both an increased peak and a slower decline suggests that they may have impaired plasma clearance of cortisol not revealed by 24-h urinary cortisol analysis.
Any of these possible mechanisms of altered cortisol secretion could be subject to programming by events in early life. Alternatively, there may be genetic determinants underlying cortisol secretion that also impact on fetal development. There are relationships between patterns of cortisol secretion and metabolism within families (33), and increased cortisol secretion has been shown to be inherited together with higher blood pressure (4). As birth weight is also at least in part inherited with higher blood pressure (34), and as increased glucocorticoid exposure in utero can lead to low birth weight (13), a genetic alteration in cortisol secretion could explain associations between birth weight and subsequent hypertension without the need to invoke programming.
By contrast with cortisol measurements in low birth weight men, our
data show that obesity is associated with lower plasma cortisol after
dexamethasone treatment and no difference in responses to ACTH-(1–24)
in the face of increased urinary cortisol metabolite excretion,
especially of 5-reduced metabolites of cortisol. The lower plasma
cortisol may be explained by increased peripheral metabolism of
cortisol by 5-reductases (35). Indeed, increasing
obesity and its associated increase in lean body mass (reflected in
higher creatinine excretion) among high birth weight men confounded the
relationship between birth weight and urinary cortisol metabolite
excretion. This confounding effect resulted in a U-shaped unadjusted
relationship between birth weight and cortisol metabolites, as
described previously (18). Although obesity may amplify
the metabolic syndrome and its association with low birth weight
(36), these data suggest that primary changes in cortisol
in the lean insulin resistance syndrome are not the same as those in
primary obesity.
In conclusion, these data suggest that men with the cluster of cardiovascular risk factors that includes low birth weight and the adult metabolic syndrome have activation of the HPAA. This may be a key mechanism to explain the relationship between low birth weight and subsequent cardiovascular disease and may offer novel therapeutic strategies to reduce cardiovascular risk.
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Acknowledgments |
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Footnotes |
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2 Wellcome Clinical Training Fellow.
3 British Heart Foundation Senior Research Fellow.
Received May 15, 2000.
Revised July 7, 2000.
Accepted September 22, 2000.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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J. R. SECKL and M. J. MEANEY Glucocorticoid Programming Ann. N.Y. Acad. Sci., |
,
7.5 lb (3.41 kg); 
, 8.5 lb (3.86 kg); *, 9.5 lb (4.31 kg); 
,
>9.5 lb (4.31 kg).