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. 26
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Weinstein, S. P., Wilson, C. M., Pritsker, A. and Cushman, S. W. (1998). Dexamethasone inhibits
insulin-stimulated recruitment of GLUT4 to the cell surface in rat skeletal muscle.
Metabolism, 47, 3“6.
141 Fetal HPA activation, preterm birth and postnatal programming


Weinstock, M., Matlina, E., Maor, G. I., Rosen, H. and McEwen, B. S. (1992). Prenatal stress
selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat.
Brain Res., 595, 195“200.
Weinstock, M. (1996). Does prenatal stress impair coping and regulation of hypothalamic“
pituitary“adrenal axis. Neurosci. Biobehav. Rev., 21, 1“10.
Welberg, L. A. M., Seckl, J. R. and Holmes, M. C. (2000). Inhibition of 11 -hydroxysteroid dehy-
drogenase, the fetal-placental barrier to maternal glucocorticoids, permanently programs
amygdala GRmRNA expression and anxiety-like behaviour in the offspring. Eur. J. Neurosci.,
12, 1047“54.
Welberg, L. A. M. and Seckl, J. R. (2001). Prenatal stress, glucocorticoids and the programming
of the brain. J. Neuroendocrinol., 13, 113“28.
Whittle, W. L., Holloway, A. C., Lye, S. J., Gibb, W. and Challis, J. R. G. (2000). Prostaglandin
production at the onset of ovine parturition is regulated by both estrogen-independent and
estrogen-dependent pathways. Endocrinology, 141, 3783“91.
Wintour, E. M., Brown, E. H., Denton, D. A., Hardy, K. J., McDougall, J. G., Oddie, C. J. and
Whipp, G. T. (1975). The ontogeny and regulation of corticosteroid secretion by the ovine
foetal adrenal. Acta. Endocrinol. (Copenh)., 79(2), 301“16.
Wintour, E. M., Smith, M. B., Bell, R. J., McDougall, J. G. and Cauchi, M. N. (1985). The role of
fetal adrenal hormones in the switch from fetal to adult globin synthesis in the sheep.
J. Endocrinol., 104(1), 165“70.
Wolf, G. (2002). Glucocorticoids in adipocytes stimulate visceral obesity. Nutr. Rev., 60, 148“51.
Yarbrough, D. E., Barrett-Connor, E., Kritz-Silverstein, D. and Wingard, D. L. (1998). Birth
weight, adult weight, and girth as predictors of the metabolic syndrome in postmenopausal
women: the Rancho Bernardo Study. Diabetes Care, 21, 1652“8.
Young, I. R., Loose, J. M., Kleftogiannis, F. and Canny, B. J. (1996). Prostaglandin E2 acts via
hypothalamus to stimulate ACTH secretion in the fetal sheep. J. Neuroendocrinol., 8, 713“20.
5


Prenatal glucocorticoids and the
programming of adult disease
Jonathan R. Seckl, Amanda J. Drake and Megan C. Holmes
Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK




˜The Child is Father of the Man™, wrote British poet William Wordsworth (1807),
re¬‚ecting upon the consistency of an individual™s emotional responses through the
long human lifespan. Soon afterwards, Mendelian and Darwinian genetics and the
still controversial concept of early life programming indicated plausible biological
bases for Wordsworth™s artistic muse. Now, nearly two centuries later, many readily
accept that part of our individual emotional compass is constrained by events affect-
ing the development of the brain before birth, effects that persist for life, de¬ning
parameters upon which nurture and the adult environment exert their modifying
effects. For genetics, the effects of classically inherited genes and chromosomal vari-
ation con¬rm the fundamental nature of inheritance of traits. Here we address the
role of a speci¬c aspect of the early life environment upon the lifelong characteristics
of an individual, a much more recent addition to understanding of ˜ease or disease™
through our span.


Epidemiology and the concept of ˜programming™

To begin, in appropriate recent historical sequence, with human epidemiology.
Numerous studies, initially in the UK and then encompassing much of the world,
have demonstrated an association between lower birth weight and the subsequent
development of the common cardiovascular and metabolic disorders of adult life,
namely hypertension, insulin resistance, type 2 diabetes and cardiovascular disease
deaths (Barker, 1991; Barker et al., 1993a, b; Fall et al., 1995; Yajnik et al., 1995;
Curhan et al., 1996a, b; Leon et al., 1996; Lithell et al., 1996; Moore et al., 1996; Forsen
et al., 1997; RichEdwards et al., 1997). The association between birth weight and later
cardio-metabolic disease appears to be largely independent of classical lifestyle risk
factors such as smoking, adult weight, social class, alcohol and lack of exercise, which
are additive to the effect of birth weight (Barker et al., 1993a). The studies suggest
that these relationships are generally continuous and represent birth weights
142
143 Prenatal glucocorticoids and the programming of adult disease


within the normal range, rather than severe intrauterine growth retardation, mul-
tiple births or very premature babies (Barker, 1991; Barker et al., 1993a; Curhan
et al., 1996a, b). However, premature babies also have increased cardiovascular risk
in adult life (Irving et al., 2000). Additionally, postnatal catch-up growth also appears
to be predictive of the risk of adult cardiovascular disease (Barker, 1991; Osmond
et al., 1993; Levine et al., 1994; Leon et al., 1996; Forsen et al., 1997; Bavdekar et al.,
1999; Law et al., 2002), suggesting that it is the restriction of intrauterine growth
rather than smallness itself which is important. Whilst such effects might re¬‚ect
classical genetic actions, some work has suggested that the smaller of twins at birth
has higher blood pressure in later life (Levine et al., 1994), although this has not
been a consistent ¬nding (Baird et al., 2001).
These early life effects are important predictors of adult morbidity (Barker et al.,
1990; Curhan et al., 1996a, b). In the Preston study, a small baby with a large placenta
had three times the relative risk of adult hypertension compared with a large baby
with a normal placenta (Barker et al., 1990). In a study of 22,000 American men,
those born lighter than 5.5 lb had increased relative risks of adult hypertension
(1.26) and type 2 diabetes (1.75) compared with average birth-weight adults
(Curhan et al., 1996b). Similarly, lighter but otherwise normal babies of 71,000 US
nurses had a relative risk of 1.43 of developing adult hypertension (Curhan et al.,
1996a). Whilst there is still debate as to the importance of birth weight in determin-
ing later disease (Huxley et al., 2002) as well as the magnitude of any such effect (it
has been suggested that some studies linking lower birth weight with higher adult
blood pressure fail to take into account the impact of random error and may involve
inappropriate adjustment for confounding factors (Huxley et al., 2002)), the mass of
human epidemiological data and the production of animal models show that early
life environmental manipulations produce persisting adult effects in both inbred
and outbred species under controlled conditions, which suggest that discrete pre-
natal events may have permanent effects on adult biology.
It is also important to consider that birth weight is an unsophisticated and blunt
measure of a disadvantageous intrauterine environment. It is therefore not surpris-
ing that birth weight associates poorly with adult pathophysiology in some studies.
Indeed the remarkable thing is that any link has been established at all, given the
crude measure of fetal challenge employed, its typically inaccurate assessment in
practice and the extensive time span between the early life insult and the adult
pathology examined. So how can we mechanistically explain such an unanticipated
association between events at either end of the lifespan?

Programming
To explain the apparent association of fetal growth and later disease, the idea of
early life physiological ˜programming™ or ˜imprinting™ has been advanced (Barker
144 J. R. Seckl et al.


et al., 1993a; Edwards et al., 1993; Seckl, 1998). Programming re¬‚ects the action of
a factor during sensitive periods or ˜windows™ of development to exercise organiza-
tional effects upon developing tissues that persist throughout life. Of course, different
cells and tissues are sensitive at different times, so the effects of environmental chal-
lenges will have distinct effects depending not only the challenge involved but also
upon its timing.
Two major environmental hypotheses have been proposed to explain the mecha-
nism by which low birth weight is associated with adult disease: fetal undernutri-
tion and overexposure of the fetus to glucocorticoids (Barker et al., 1993a; Edwards
et al., 1993; Seckl, 1998). A third perhaps complementary hypothesis suggests that
genetic factors may lead to both low birth weight and subsequent risk of cardiovas-
cular disease (Figure 5.1). Indeed, loci have been described which may link small-
ness at birth with adult disease (Dunger et al., 1998; Hattersley et al., 1998; Vaessen
et al., 2001). Whilst the putative loci implicated relate to biologically plausible can-
didate genes such as insulin, insulin-like growth factors (IGF) and their signalling
pathways, as well as other key metabolic regulators such as 3-adrenoceptors, per-
oxisome proliferator-activated receptor (PPAR ) and tumour necrosis factor alpha
(TNF ) (Jaquet et al., 2002), there remains debate as to reproducibility of ¬ndings
(Frayling et al., 2002), perhaps because studies have been underpowered (Frayling
and Hattersley, 2001). So the relative importance of genetic and environmental
factors in the ˜low-birth-weight baby syndrome™ remains unknown. However, the
occurrence of associations between early life environmental manipulations and
later physiology“disease risk in isogenic rodent models and, less certainly, the birth-
weight“adult-disease associations in human twins implicate environmental factors,
at least in part, in aetiology. Here the speci¬c issue of hormonal programming by
glucocorticoids is considered.


Possible mechanisms (non-exclusive)


• Genetics
• Uterine size
• Maternal malnutrition
• Growth factors (IGFs, insulin)
• Glucocorticoids
“ Reduce birth weight in mammals CH2OH
8.5 lb 5.5 lb “ Alter organ maturation C O
HO
“ Directly cause: hypertension,
Two full-term babies born to healthy, non-
diabetes, osteoporosis, etc.
smoking, unmedicated mothers on the same
“ Sex steroids ˜programme™ O
day in the same hospital. The smaller, thinner
baby on the right has a substantially increased
risk of cardio-metabolic disease in adulthood

Figure 5.1 Birth weight and adult disease: possible mechanisms
145 Prenatal glucocorticoids and the programming of adult disease


Glucocorticoid programming

Steroids and organizational effects
Steroid hormones have long been associated with organizational actions. It is
well documented that neonatal exposure to androgens programme expression
of hepatic steroid metabolizing enzymes, the development of sexually dimorphic
structures in the anterior hypothalamus and sexual behaviour in many vertebrate
species including mammals (Arai and Gorski, 1968; Gustafsson et al., 1983).
Estrogens also exert organizational effects on the developing central nervous system
(CNS) (Simerly, 2002). Critically, these effects can only be exerted during speci¬c
perinatal periods, but then persist throughout life, largely irrespective of any subse-
quent sex steroid manipulations. The mechanisms re¬‚ect sex steroid actions on the
growth, maturation and remodelling of organs during critical perinatal periods. In
the rat, the sexually dimorphic nucleus of the preoptic hypothalamic area is larger
in males. Testosterone inhibits apoptosis speci¬cally between postnatal days 6 and
10 and selectively in this locus, thus producing the male adult phenotype (Davis
et al., 1996).


Why glucocorticoids?
Glucocorticoids and birth weight
In addressing the link between birth weight, which surely is merely a marker of an
adverse intrauterine environment, and adult cardio-metabolic disorders, glucocor-
ticoids are attractive candidate aetiological factors (Seckl, 1994; 1998) (Figure 5.1).
For decades it has been observed that glucocorticoid therapy during pregnancy
reduces birth weight in animal models, including non-human primates (Reinisch
et al., 1978; Ikegami et al., 1997; Nyirenda et al., 1998; French et al., 1999; Newnham
et al., 1999; Newnham and Moss, 2001). Such effects are the most powerful in the
latter stages of pregnancy (Nyirenda et al., 1998), presumably re¬‚ecting the catabolic
actions of these steroids, which is most manifest during the phases of maximum
fetal somatic growth.
In human pregnancy, glucocorticoids are now only widely used in the manage-
ment of women at risk of preterm delivery and in the antenatal management of
fetuses at risk of congenital adrenal hyperplasia. In some such populations ante-
natal glucocorticoids are associated with a reduction in birth weight (French et al.,
1999; Bloom et al., 2001), although normal birth weight has been reported
in infants at risk of congenital adrenal hyperplasia whose mothers received
low-dose dexamethasone in utero from the ¬rst trimester (Forest et al., 1993b;
Mercado et al., 1995b). A recent study of pregnant women with asthma did not
¬nd changes in birth weight with use of inhaled and/or episodic oral glucocorti-
coids. Indeed, a lack of glucocorticoid treatment was associated with a reduction
146 J. R. Seckl et al.


in offspring birth weight (Murphy et al., 2002). However, the effects on placental
function of in¬‚ammatory mediators in poorly controlled asthma, the predom-
inant topical route of steroid administration and the use of prednisolone which
is rapidly inactivated by placental 11 -hydroxysteroid dehydrogenase type 2
(HSD-2) and poorly accesses the fetal compartment (see below) might explain
these ¬ndings.
For endogenous glucocorticoids, human fetal plasma cortisol levels are increased in
intrauterine growth retardation or in pre-eclampsia, implicating endogenous cortisol
in retarded fetal growth (Goland et al., 1993; 1995). Cortisol also affects placental
size, at least in animals, the effect dependent of the dose and timing of exposure
(Gunberg, 1957).

Glucocorticoids and tissue maturation
Glucocorticoids have potent effects upon tissue development. Indeed it is the
accelerated maturation of organs notably the lung (Ward, 1994) which underpins
their widespread use in obstetric and neonatal practice in threatened or actual
preterm delivery.
Underpinning such actions, glucocorticoid receptors (GR), which are members of
the nuclear hormone receptor superfamily of ligand-activated transcription factors,
are expressed in most fetal tissues from early embryonal stages (Cole, 1995).
Expression of the closely related, higher-af¬nity mineralocorticoid receptor (MR)
has a more limited tissue distribution in development and is only present at later
gestational stages, at least in rodents (Brown et al., 1996a). Additionally, GR are highly
expressed in the placenta (Sun et al., 1997) where they mediate metabolic and anti-
in¬‚ammatory actions. Clearly systems to transduce glucocorticoid actions upon
the genome exist from early developmental stages, with complex cell-speci¬c pat-
terns of expression and presumably sensitivity to the steroid ligands.

Glucocorticoids and the low-birth-weight baby syndrome
The major systems affected in the ˜low-birth-weight baby syndrome™ are
glucocorticoid-sensitive targets. Notably the syndrome is broadly familiar to
endocrinologists since it resembles the Cushing™s syndrome/metabolic syndrome
continuum of inter-associated cardiovascular risk factors (type 2 diabetes/insulin
resistance, dyslipidemia, hypertension) linked by circulating or tissue glucocorti-
coid excess (Seckl and Walker, 2001). Even the less well-recognized components of
the small baby syndrome such as osteoporosis (Gale et al., 2001) are also key fea-
tures of Cushing™s syndromes. Moreover, at least a proportion of these physiologi-
cal systems are also glucocorticoid sensitive in early life since cortisol also elevates
fetal blood pressure when infused directly in utero in sheep (Tangalakis et al.,
1992) and at birth in sheep (Berry et al., 1997) and humans (Kari et al., 1994).
147 Prenatal glucocorticoids and the programming of adult disease


Physiology: placental 11 -HSD-2
All the points above relate to pharmacological glucocorticoid exposures or tissue
sensitivity. However, study of the latter led to an understanding of a possible physio-
logical basis of glucocorticoid overexposure in utero.
Whilst lipophilic compounds such as steroids are thought to cross the placenta
rapidly, fetal glucocorticoid levels are much lower than maternal levels (Beitens
et al., 1973; Klemcke, 1995). This is thought to be due to 11 -HSD-2 (Figure 5.2)
which is highly expressed in the placenta. 11 -HSD-2 is an NAD-dependent 11 -
dehydrogenase which catalyses the rapid metabolism of the active physiological
glucocorticoids cortisol and corticosterone to their inert 11-keto forms, cortisone and
11-dehydrocorticosterone (White et al., 1997). It is 11 -HSD-2 that excludes gluco-
corticoids from intrinsically non-selective MR in the distal nephron where the enzyme

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