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					Low birth weight and endocrine dysfunction in postnatal life




Maria Veronica Mericq G. MD
Associate Professor
Institute of Maternal and Child Research
Faculty of Medicine
University of Chile
El Encuentro 240,
Altos La Foresta,
Las Condes
Santiago, CHILE




Table of Contents

I.    Introduction
II. Genetic Factors of Fetal Growth
III. In Utero Programming
   A. Programming Evidence
   B. Programming Mechanisms
IV. Post-natal Programming of Endocrine Dysfunction
V. Mechanisms of development of Insulin Resistance
VI. Gonadal & Adrenal Axis
VII. Somatotropic Axis
VIII Conclusions
       Referentes, Tables & Figures
   I.     Introduction


   Small size at birth has long been recognized to increase neonatal morbidity and
   mortality. As early as 1962 J.V. Neel a population geneticist proposed that
   changes of in utero environment made to guarantee survival during adverse
   conditions could become harmful during nutrition abundance [1]. This concept
   is now well established. Reduced growth in early life is strongly linked with a
   number of endocrine dysfunctions.          Included among the most important
   alterations are insulin insensitivity, gonadal and somatotropic axis abnormalities
   and premature adrenarche        [2, 3]]   . These have been associated with an
   escalating prevalence of Type 2 Diabetes Mellitus (T2DM) [4]. Coronary Heart
   Disease (CHD) [5], abnormal gonads and genitalia           [6]-9], growth hormone
   resistance and decreased growth [7] 11], as well as early puberty [8]. The
   usual hypothesis proposed to explain the development of these long term
   alterations relates to the thrifty phenotype as an adaptive response to in utero
   malnutrition [9] and modifications thereof; initially termed “Fetal Origins” [10]
   and updated to “Developmental Origins” which include the additional
   contributions of the patterns of growth in infancy and childhood [11].
   Throughout this chapter we review the current knowledge of the programming
   of the fetus and infant that lead to endocrine dysfunction in postnatal life .




II. Genetic Factors of Fetal Growth


Fetal growth is a delicate controlled process influenced by hormones, growth
factors and the intrauterine milliue. Examples of some variables that affect fetal
growth are chromosomal abnormalities, genetic diseases, maternal alterations
(TORCH, Hypertension, nutrition, Tobacco, collagen diseases), placental and
demographic factors.     The mechanisms that participate in the regulation of size
at birth and the later consequences of the intrauterine insult are shown in Figure 1.
Insulin trophic actions play a key role in the regulation of fetal growth; this is
evidenced by the severe intrauterine growth impairment occurring in congenital
mutations of the insulin structure or of the insulin pathway function (1-3)and by the
reduced size of the fetus present at birth in infants with specific gene mutations
(11-13). The opposite picture develops in diabetic hyperglycemic mothers who
give birth to large for gestational age infants, as a result of chronic in utero fetal
hyperinsulinism that develops to compensate for maternal glycemic fluxes.
Experimental models that retard fetal growth in rats induce modifications of glucose
utilization in several fetal tissues [12],20]. In addition, insulin like growth factors
(IGF’s) and their binding proteins (IGFBP’s), are involved in the regulation of fetal
growth [13]. In fact the mechanisms of action of IGF’s and insulin are shared at
several levels in the cell [14]. Models that attempt to explain the association of low
birth weight and postnatal diseases, consider as central, the action of insulin and
related peptides [10],[15]. Genetically programmed low energy consumers would
present resistance to anabolic hormones such as insulin [16]. However, no
mutation has been identified to explain the strong highly prevalent linkage to insulin
resistance genes [17].



The candidate genes associated with reduced size at birth are shown in Table 1.
These include homozygote or compound heterozygous insulin receptor
mutations causing Leprechaunism [18], Insulin promoter factor –I [IPF1]
mutation with pancreatic agenesis [19] and heterozygous glucokinase
mutation [20]. These mutations may involve alterations in any of the factors that
belong to the family of growth receptors with intrinsic tyrosine kinase activity,
including the Insulin receptor (IR), Insulin like growth factor (IGF-I), its receptor
(IGF-I-R)   and the hybrid IR/IGF-I-R [21].         These lead to signaling pathway
alterations in insulin action and constitute molecular targets of insulin resistance
[22]. The cellular effectors of insulin participate in intermediary metabolism and in
cell proliferation, a disruption in action results in insulin resistance [22], 28].
The pattern of insulin secretion per se is able to modify the response of peripheral
tissues to this hormone [23]. A relevant factor that determines the pattern of insulin
secretion is the short term insulin gene transcription by glucose in the late phase of
Beta cell response [24]. In vitro the gene promoter of variable number of tandem
repeat (VNTR) alleles of insulin is able to modify its transcriptional activity through
the Pur-1 factor [25]. These molecular findings have clear clinical correlations that
associate allelic variants of VNTR in the insulin gene with Diabetes Mellitus (DM),
as well as reduced size at birth [26], [27]. In Caucasian populations the most
frequent allelic VNTR at the insulin gene minisatellite locus (type I) is associated
with an increased risk for type 1 DM (T1DM); whereas the type III allelic VNTR is
associated with T2DM, obesity and ovarian hyperandrogenism [26], [28]. The type
III allele is also associated with increased birth weight [27] . We recently
demonstrated a greater insulin secretion after an intravenous glucose infusion
(IVGGT) in a cohort of term 1 year old infants who had the type III allelic VNTR
[29]. A second candidate gene, the one encoding calpain (CAPN10), was also
identified as being responsible for the T2DM association with the 1 locus in
chromosome 2 [30]. Other genes that have been proposed to be involved in the
association of low birth weight (LBW) and later insulin resistance include IGF-1,
IRS-1, Glucokinase,      H19, pre-adipocyte factor-1 and growth factor receptor-
bound proteins (GRB-10) which           constitute a family of structurally related
multidomain adapters with diverse cellular functions which have been implicated in
the regulation of insulin receptor signaling [20] [31].


III. In utero programming


Several authors have proposed the existence of a prenatal metabolic programming
which would promote the development of a “thrifty phenotype” (9). A poor
intrauterine nutrition would determine an endocrine adaptation designated to
sustain the development of more sensitive organs, such as the central nervous
system. This response consist mainly of the inhibition of anabolic factors (insulin
and IGFs) in muscle, adipose and connective tissues, during the time of need,
which would persist into adult life [10]. In animal models there are some examples
of prenatal adaptations, which persist into postnatal life [32], [33]. However, in
humans there is no direct evidence to support this theory.


A) Programming Evidence


Various experimental models have been utilized to study the potential in utero
programming mechanisms of a thrifty phenotype. Nutritional restriction of the
pregnant animal, in terms of total calories or protein deprivation is a model that has
been utilized to test this hypothesis [32]. The human extension of these results has
been controversial [34] , since LBW due to maternal nutrition deprivation is rare in
the occidental world. Another model employed has been the restriction of oxygen
delivery to the placental-uterine bed. This model exposes to low oxygen tension in
the environment the pregnant animal [35] . This model is clearly a not applicable to
humans.

Wigglesworth developed a model in rats, which limits the utero-placental oxygen
delivery [36], has also been applied to sheep [37]. In this model partial or total
stretching of the uterine artery (s) during the last part of gestation is used. Recent
modifications to the technique apply repeated embolization of uterine vessels [38]
and systemic use of vasoconstrictor agents such as tromboxan [39]. These
maneuvers have been used to better reflect what occurs in intrauterine growth
restriction (IUGR) due to placental dysfunction , which is the most common cause
of small for gestational age deliveries (SGA)( 50%) [40].

In spite of the differences between the above experimental models, the data have
been consistent and provide evidence of the fetal and new born metabolic
consequences of the adverse intrauterine environment. Both protein caloric
restriction and vascular supply, produce a fetus and new born that develops
hypoglycemia, hypoaminoacidemia and hypoinsulinemia, among the most
important metabolic consequences [41], [42]. Hypoinsulinemia correlated with the
alterations in the development of beta cells in the Langerhans islet [43],[44].
However there was no glucose intolerance and the glucose uptake in peripheral
tissues (muscle and adipose) [45], and insulin/glucose ratios in fetuses and
newborns, indicated that there was a greater insulin sensitivity compared to
control animals [41],[42] .These findings are in agreement with limited human data
provided by chordocentesis [46] .



These experimental data have led some authors to cast a note of caution about the
Barker’s hypothesis, which considers the development of insulin resistance during
fetal life [10]. Alternatively, it could also be that the resistance is specific to certain
tissues. In fact that is what has been shown when protein restrictive models are
used; namely changes of expression in glucose transporter (GLUT) family proteins
in adipose, muscle and nervous tissues [47]. The applicability of these findings to
humans was demonstrated [48].


B) Programming Mechanisms


Insulin sensitivity might be altered during fetal life as a response to endocrine
modifications following an adverse intrauterine environment (Figure 2). One such
modification could be the increased levels of circulating cortisol, a counter-acting
hormone to insulin. In addition the hyperactivity of the hypothalamic-pituitary-
adrenal axis as a consequence of fetal stress [49]-[50] may be attributable to a
decreased activity of the placental enzyme 11ß-hydroxysteroid dehydrogenase
(11ß-HSD) which degrades cortisol and thereby alters the maternal impact of the
fetal compartment[51]. The enhancement of cortisol levels would act in several
tissues, including the liver which is key in determining insulin sensitivity [52]. TNF-
α, is also able to induce insulin resistance in several tissues [53] . In fact a certain
polymorphism in the promoter region of the TNF-α gene has been linked to the
development of insulin resistance in adults [54]. Elevated TNF levels are present
in fetal blood in several fetal stress situations, such as premature delivery and
intrauterine infection [55].
The initial associations of LBW with a decrease in insulin sensitivity were
established in studies performed in Hertfordshire, England. In the first studies 5654
men born between 1911 and 1948 whose birth weights and subsequent growth
until 1 year of age had been registered, were retrospectively analyzed. In this
population those with the lowest birth weight had the highest mortality rates due to
cardiovascular disease [5]. From the same population 468 men had a fasting
glucose determination and 370 had a complete OGTT; 40% of men with birth
weights equal or below 2,5 kg had a glycemia at 2 and 4 hours of 140 mg/dl or
more compared with only 14% of men born with the highest weights [56].
Subsequently other retrospective studies documented the presence of the other
components      of   the    metabolic     syndrome;     i.e.   hypertension,     and
hypercholesterolemia [57, 58]. These studies confirmed the greater risk of this
disease when LBW was present [59, 60].


Some of these observations were replicated in different countries and populations
of different backgrounds. In India a study of 517 adults found that the prevalence of
CHD was 11% in those with LBW of less than 2500 g whereas in those with a birth
weight of 3100 grs or more it was 3%. These associations were independent of
other variables associated to CHD such as life style [60], [61]. The association of
T2DM and glucose intolerance with CHD and hypertension suggested that insulin
resistance could be present in LBW infants.




IV. Post-natal programming of endocrine dysfunction.


One of the main limitations of the above mentioned studies is the retrospective
analysis where birth weight is related to the metabolic status or complications
detected in later life. These studies did not take into account early growth and
metabolic changes that occurred after birth. Since 1998 a number of authors have
proposed that postnatal growth of LBW children, as characterized by the body
mass index (BMI) at 7-8 years of life, might be an independent factor determining
insulin sensitivity [62]-[15, 63, 64].   This hypothesis was confirmed in a term
cohort of LBW Chilean children [65]. Insulin resistance could be programmed in the
early postnatal life during the catch-up growth (CUG) phase shown by SGA
infants. During this phase of CUG there is an increase in the levels of several
anabolic hormones; such as; insulin and related peptides (IGFs) [66]. Insulin
resistance could initially develop in SGA to counteract their tendency to
hypoglycemia, and would then persist during their entire life. CUG could also lead
to a disproportionate increase of fat compared to lean mass acquisition [67, 68].
Some authors propose that suppressed thermo genesis leads to this unequal
distribution of fat and lean mass during the CUG period [67]. This theory has
gained more acceptance because of the current epidemiological data of the
explosive worldwide increase in T2DM           which has specially affected those
countries where LBW is more prevalent [69].


Ong. et al in the ALSPAC (Avon longitudinal study of pregnancy and childhood)
cohort also showed that early catch up growth predicted increased body fat mass
and central fat distribution at 5 years of age [70]. We demonstrated that at one,
two and three years of age, insulin secretion and sensitivity were related to the
patterns of catch-up growth. Fasting insulin sensitivity was more closely related to
weight catch-up growth and current BMI, whereas insulin secretion appeared to be
directly related to length catch-up growth [65]. These data were in accordance with
previous studies that showed that at later stages of life those born SGA with early
CUG have a greater risk of Syndrome X [71]. Recently a prospective study of the
ALSPAC cohort which included term newborns with a large variation of normal
birth size confirmed these observations. At 8 years of age, those who were lighter
and grew faster in early life were the most insulin resistant among the cohort [72].
Erikson et al analyzed the influence of early catch up growth and birth weight in
CHD deaths [63]. Greater mortality rates were present among those subjects who
were lighter at birth, but had a normal or increased BMI at of 7 years of age.
In a pioneering pediatric study by Hoffman et al. insulin sensitivity was studied
through a   long IV glucose tolerance test in prepubertal short stature children,
either born SGA or appropriate for gestational age (AGA) [73]. This method
allowed the detection of a significant difference in insulin sensitivity; those born
SGA had an increased acute phase of insulin release (445 vs.174 ug/ml). Early
changes in insulin sensitivity, secretion, and lipid metabolism were associated with
being born SGA at term [81]. During the first 48 hrs of life SGA infants displayed
increased insulin sensitivity with respect to glucose disposal, but showed
suppression of lipolysis, ketogenesis, and hepatic production of IGFBP-3 as
compared with AGA children.


One element of the puzzle not previously clarified was whether the decrease in
postnatal insulin sensitivity in SGA children was present only when the adverse
condition was present in utero or could also develop when adverse postnatal
conditions were present, as in the case of an extremely premature birth. It has
been suggested that postnatal morbidity during a critical period of rapid growth
might contribute to the metabolic modifications observed in LBW children,
independently of the adequacy of their birth weight to gestational age. Another
question was the effect of prematurity per se, since in most studies the birth weight
had been evaluated independently of gestational age or preterm infants were
excluded. Therefore the link between LBW and postnatal insulin resistance was
assessed regardless of gestational age [63, 74, 75]. The effects of current BMI,
birth weight standard deviation score (SDS), postnatal growth rates, and indicators
of postnatal morbidity were evaluated in twenty SGA and 40 were AGA very low
birth weight (VLBW) children (birth weight between 690-1500 g. gestational age
25-34 weeks). They were evaluated at 5-7 years of age by a short intravenous
glucose tolerance test (IVGTT). In this cohort of premature, VLBW children, IUGR
rather than LBW was associated with reduced sensitivity to insulin. This link was
independent of gestational age and other indicators of postnatal stress. In addition,
fasting and first-phase insulin secretion were related to postnatal growth rates,
which was in accordance with our previous observations [76]. However an opposite
finding was reported by Hofman et. al. but in their report no comments of the
interaction of growth in utero and postnatal growth was described. In addition, the
New Zealand cohort was rather small and children had short stature [77].


Several gene polymorphisms involved in the control of intermediary metabolism,
such as the insulin gene variable number of tandem repeat (INS VNTR) alleles and

Ghrelin C247A(y) leptin C-2549A in peripheral DNA were not related to growth
kinetics or to IVGTT response [29]. However, at 1 year class III/III alleles in the
INS VNTR locus were associated with increased fasting as well as post-stimulated
insulin. These findings were independent of birth weight and postnatal growth
kinetics.


One of the important and constant findings regarding the determinants of insulin
sensitivity during adulthood is that LBW is not a major determinant of later insulin
resistance, except among subjects with the largest current BMI [72]. The factors
that determine the transition from relatively low birth weight to childhood
overweight are not known, but could be mediated by increased appetite. The
regulation of food intake is a complex process involving neural and gut interactions
(Chapter____). One of the hormones involved in this interplay is Ghrelin [78] and
the specific 7 transmembrane G protein coupled receptor for this hormone present
in the hypothalamic arcuate nucleus and pituitary [79]. In animal studies the
intracerebrovascular and peripheral administration of Ghrelin induces adiposity and
increases appetite and this orexigenic activity appears to be mediated by increases
in NPY [80]. In humans, Ghrelin levels are decreased in obesity and increased in
anorexia [81].


Since most SGA infants show some degree of postnatal length and weight CUG
and since this phenomenon affects postnatal insulin sensitivity independently of
birth weight, we postulated that Ghrelin appetite effects could be involved in the
CUG. The fasting and post IVGTT circulating Ghrelin levels in SGA and AGA infants
aged 1 year were not different [82]. As seen in older children and adults, circulating
Ghrelin concentrations rapidly decreased after IV glucose. Interestingly, post-
glucose Ghrelin levels, but not fasting values, correlated positively with current
length, current weight, and change in weight. In addition, lower reductions in
circulating Ghrelin levels following IV glucose were observed in SGA infants who
showed greater weight gain during infancy, suggesting that a sustained orexigenic
drive could contribute to postnatal growth.


In the literature only one report addresses the interaction between LBW, postnatal
growth and genetic background. Jaquet et al [83] investigated the role of several
polymorphisms which modulate insulin sensitivity: Proala12 in PPARγ, G+250C in
the β3 adrenergic receptor, G-308A in TNFα. They genotyped 171 adult’s who were
born SGA and 233 who were born AGA, submitted to an oral glucose tolerance test
(OGTT). The SGA group showed higher serum insulin concentrations at fasting and
during stimulation and their fasting glucose- insulin ratios were significantly higher in
the TNF/-308,PPAR/ala12 and ADRB3/+250G carriers. Moreover, the effects of
these polymorphism on insulin resistance indexes were significantly potentiated by
current BMI in the SGA group.[83]. In neither the SGA nor AGA group did the
polymorphisms affect glucose tolerance.


V. Mechanisms of development of Insulin resistance in SGA subjects


In young adults with a normal BMI and a similar fat mass, glucose oxidation rate
and uptake were diminished in those born SGA as compared with those subjects
born AGA [84] . In SGA, a decreased expression of glut-4 in muscle and adipose
tissues during an euglycemic hyperinsulinemic clamp was detected [48]. Glucose
uptake was also reduced during an euglycemic hyperinsulinemic clamp in 8 year
old children [73]. These findings reinforce the concept of abnormal glucose
transport as an important element in the control of insulin sensitivity. Recently, a
study performed in offspring of young, lean patients with T2DM              showed an
increase in intramyocellular lipid content,         concomitant with impairment of
mitochondrial activity in those who were insulin resistant versus insulin sensitive
patients [85] .


 The adipocyte has been shown to be an active cell that secretes bioactive
molecules, termed adipokines [86], [87]. The molecules produced by the
adipocyte have autocrine and paracrine actions. These include leptin, tumor
necrosis factor-∝(TNF-∝), plasminogen activator inhibitor type 1 (PAI-1) and
adiponectin. Adiponectin is a 244 amino acid protein, product of the most
abundant gene transcript-1 (apM1) expressed in human adipose tissue [88].
Recently two adiponectin receptors have been described: adiponectin receptor-1
abundantly        expressed   in   skeletal   muscle;   and   adiponectin   receptor-2
predominantly expressed in liver [89]. Several studies have demonstrated that
adiponectin modulates glucose tolerance and insulin sensitivity [90-92]. In animal
models this protein decreased circulating free fatty acids by increasing oxidation in
muscle and decreasing uptake in liver, with subsequent lower plasma triglyceride
levels [93]. It also directly activates glucose uptake in adipocytes and muscle
through AMP protein kinase. In humans, adiponectin levels predict subsequent
changes in insulin resistance, but not lipid profiles or body weight [94, 95].
Adiponectin mRNA is decreased in the adipose tissue of obese and diabetic
patients, but is restored to normal levels after weight loss. Increases in
adiponectin levels have been described after weight loss in obese and diabetic
subjects. In adult Pima Indians, higher plasma adiponectin levels appeared to
protect against the development of T2DM [96]. In a small sample of 5 to 10 year
old children, hypoadinectinemia appeared to be the consequence of obesity, but
no associations with insulin sensitivity were found [97].


However, it is difficult to assess the effects of weight gain and insulin sensitivity
from small cross sectional studies. We therefore determined whether adiponectin
levels were related to patterns of postnatal growth and insulin sensitivity in a
prospective cohort of infants followed from birth to two years [98] . Serum
adiponectin levels at 1 year and 2 years were higher compared with reported
levels in adults and older children and were significantly decreased from 1 to 2
years. At 2 years adiponectin levels were lower in females as compared with
males, but no gender differences were seen in leptin and insulin levels. Also no
differences existed in adiponectin levels between SGA and AGA infants at 1 year
or 2 years. However, in SGA infants the changes in adiponectin levels from year 1
to year 2 were inversely related to weight gain. .Adiponectin levels were not
related to insulin levels at 1 or 2 years, nor to change in insulin levels. Multiple
regression analysis revealed that adiponectin levels were only related to postnatal
age. Other determinants of higher adiponectin levels were male gender, lower
postnatal body weight, and higher birth weight SDS. In conclusion, changes in
serum adiponectin levels during the first 2 years of life were related to patterns of
weight gain in SGA infants, but not to early changes in insulin sensitivity [98].


VI. Gonadal and Adrenal Axis


The child born small is at increased risk for abnormalities of the gonads and
genitalia. Francois et al showed that unexplained, severe hypospadias was related
either to restraint of prenatal growth or to complications in early pregnancy [99].
This evidence has been supported by the data of Nordic countries where
cryptorchidism as well as hypospadias have been found more frequently in SGA
babies [100, 101].
A conclusive support for the concept of non-genetic pseudo-hermaphroditism was
presented by De Zegher et al [6]. This report of a pair of monozygotic twins whose
gestation was supported by one placenta. The twins were discordant for birth
weight and for male differentiation. Detailed studies revealed no evidence for any
endocrinopathies. The genitalia of the AGA male were normal, while the SGA had
perineal hypospadias and testes in labia-scrotal folds. It is difficult to conceive an
experiment whereby a genetic cause of male pseudohermaphroditism could be
more convincingly excluded.
Almost half a century ago, Henry Silver noticed that some men who were born
small tended to have high urinary gonadotropins levels and to have small testes
[102]. This was the first observation indicating that prenatal growth restraint may be
followed by reduced Sertoli-cell function and by sub-normal spermatogenesis.
More recently Ibañez et al assessed the serum concentrations of inhibin B to
determine whether there was a relation between reduced prenatal growth and
subsequent Sertoli-cell dysfunction in infancy [109]. SGA boys needed a higher
FSH drive to generate the normal feedback level of inhibin B.
Premature adrenarche, the prepubertal rise in the secretion of adrenal steroids,
occurs in association with decreased insulin sensitivity in obese and in girls born
SGA [103]. The presence of premature adrenarche in SGA girls was reported in
Spain [2] and in a group of Hispanic and African American girls living in New York
[104]. A decrease in insulin sensitivity could be the drive to increased adrenal
steroidogenesis. Ibañez also postulated that CRH might be the potent adrenal
secretagogue in these girls [105] . In addition exaggerated adrenarche appears as
a risk marker of ovarian hyperandrogenism [106]. In the northern Spanish girls
evaluated by Ibanez et al. the SGA female had smaller ovaries and a smaller
uterus in adolescence and also had FSH hypersecretion, first noted during infancy
and also present later in adolescence [107],[108]. However, it is important to note
that these studies only evaluated girls from an endocrine clinic , with a similar
ethnic background. Treatment with the insulin sensitizer mertformin was tried in a
the Catalunian cohort of non obese adolescents born SGA with eumenorrheic
anovulatory cycles [109]. After only 6 weeks ovulatory cycles resumed and lipid
levels improved. A simultaneous decrease in LH, FSH, insulin and androgen levels
was noted which suggest that SGA associated anovulation is a result of
hyperinsulinism rather than adrenal & ovarian hyperandrogenism. It remains to be
elucidated whether these risks are also present in healthy girls born SGA recruited
from the community and from other ethnicities, as studies in France [110] and
Holland failed to show such an association [111] .
VII. Somatotropic axis


The fetal somatotropic axis is characterized by growth hormone resistance in the
SGA fetus. A simple way to understand the somatotropic axis of the SGA fetus is
to consider such as being in a fasting condition. SGA fetuses display low serum
levels of insulin, IGF-1, IGF-2, and IGFBP-3 and high levels of IGFBP-1, whereas
the large for gestational age infant shows high insulin and IGF-1 levels and a
reverse pattern of IGF binding proteins [7].


After birth, CUG occurs in the vast majority of SGA children [112]. Postnatal CUG
begins immediately after birth within a maximum occurring by 6 months of age. By
2 years of age, nearly 90 % of term or preterm SGA infants achieve a height within
the normal range. The age of 2 years is an important milestone: in SGA children
who were born at term, it is quite rare to observe spontaneous catch-up growth
after the age of 2 years.   Of the SGA infants who fail to show CUG by 2 years
about half remain short even in adulthood. The relative risk for being short at age
18 is 5.2 for children born light and 7.1 for children born short. Failure of CUG
could be secondary to altered action of GH, IGF-I or Insulin.
Different series show that there is an increased frequency of growth hormone
deficiency (GHD) among SGA with non CUG (35-53%) . Even when GH levels
are normal on standard stimulation tests, these children demonstrate abnormalities
in the pattern and 24 hour profile of GH , lower IGF-I and IGFBP3 [113] [114] .
Cutfield , however in a selected population of short SGA children found normal or
elevated IGF-I levels and postulated that hyperinsulinism could play a role [115] .
Possible differences among studies could be related to the heterogeneous nature
of the SGA condition and some form of IGF-I resistance present in a subset of
these children (Chapter___).
During the last decade several investigators studied the effects of therapy with
growth hormone for those SGA infants who remained small after 2 years of age.
Over the years it has become evident that GH administration improved growth
velocity, weight gain, height SDS and final height in SGA children independent of
their response to provocative testing. The height gain appears to be related mainly
to the total time of GH therapy and the dose employed [116], [117]. During GH
therapy weight gain is improved, not due to an excess of fat, but to an increase in
lean body mass shown by MRI, and serum leptin [118]. Importantly GH stimulation
testing is not a requirement previous to therapy and does not predict growth
response during therapy. These test are recommended only if GH deficiency is
clinically suspected in an SGA child in view of postnatal growth failure, poor facial
development or poor skeletal growth. Bone age is usually delayed and height
prediction is unreliable in children with SGA [119] .


In July 2001 a consensus with final FDA approval of GH therapy as an indication
for non catch up growth SGA children emerged [120]. Recent reports evaluating
the final height of SGA children treated with GH , showed that it was significantly
improved [121]. The standard dose of GH, however, is less effective in assisting
short children born SGA to achieve a sufficient CUG . THE FDA approved dose for
SGA is 0.48 mg/K/week . In Europe a lower starting dose of 0.35 mg/K/week is
recommended. The main determinants of final height are GH dose, duration of
treatment, greater family corrected initial height deficit.
In addition to improvements in height positive metabolic effects such as lower
blood pressure and beneficial effects on craniofacial development, body
composition , less atherogenic lipid profile and psychological well being have
been observed [122] .
A number of safety issues have been addressed So far, the evidence continues to
be reassuring for GH therapy in these children. In particular, GH does not seem to
increase the risk for precocious puberty or glucose intolerance. Benign cranial
hypertension , aggravation of scoliosis, jaw prominence and           mild transient
hyperglycemia have been reported in recent KIGS data. However, these adverse
events were not different from the short stature population given GH therapy
[123-125]


 VIII. Conclusions


Investigations performed during the last decade have identified the independent
association between reduced fetal growth and the later development of endocrine
dysfunction primarily manifested by gonadal, adrenal, somatropic, and metabolic
abnormalities. Insulin resistance appears to play a critical early role in at least the
adrenal and the metabolic alterations associated with frequent diseases producing
increased morbidity and mortality among adults. Data suggest that the link between
prenatal growth restriction and postnatal insulin sensitivity is already present at 1
year of age. On the other hand, IUGR rather than LBW appears to be associated
with reduced sensitivity to insulin. Finally, rapid postnatal catch-up growth appears
to contribute actively to insulin sensitivity and secretion, at least during the first
years of life. We speculate that accelerated catch-up growth during the postnatal
period may lead to the development of a metabolically disadvantaged body
composition, with an increase preferentially in body fat independent of birth weight
as has been demonstrated for other conditions where CUG occurs [67, 68] .
The importance of these data to daily clinical practice is to identify SGA as a risk
marker of Insulin resistance, and T2DM.


   On the other hand there is a clear need to reconcile the contribution of the “thrifty
phenotype” and “thrifty genotype” in the generation of adverse health outcomes
after a period of nutritional deprivation in early life. The determination of these
respective contributions will also clarify the evolutionary adaptations that improve
the likelihood of survival of a developing organism that is under duress, but may
carry a consequence for poor adult health outcomes after reproductive
senescence. It is clear that there the use of terms such as programming, plasticity
and predictive adaptative responses may each be hotly debated, particularly as
experimental and epidemiological studies investigate the impact of relative over
nutrition in prenatal life. On the other hand during postnatal life the focus of
experimental and epidemiological studies will need to investigate the role
environmental factors that modulate rapid CUG. Until these data are available we
are not in a position to recommend the types of intervention required to improve
the efficiency of the growth of these infants to minimize the risk of the morbidity
and mortality complications prevalent in adults who were born SGA.
Figure 1




ADVERSE INTRAUTERINE ENVIRONMENT                 GENES




Prenatal Programming
INSULIN RESISTANCE                              INSULIN RESISTANCE


                  LOW BIRTH WEIGHT


                         CATCH UP GROWTH


                        INSULIN RESISTANCE


                  Increased food /sedentary

                  INSULIN RESISTANCE


Glucose Intolerance Ovarian hyperandrogenism Dyslipidemia   Hypertension
Type 2 Diabetes




                              Syndrome X
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Table 1

Genes associated with reduced growth in utero “ thrifty genotype”

Homozygote or compound heterozygous insulin receptor mutations
                                                      Leprechaunism
IPF1 mutation with pancreatic agenesis                 LBW
Heterozygous glucokinase mutation                      LBW
Insulin like growth factor (IGF-I)                     LBW
Insulin like growth factor receptor (IGF-I-R)          LBW
Insulin gene:
polymorphism of tandem repeat in the promoter gene of insulin (VNTR) I/I LBW

GRB-10 & H19                                    Russell Silver (LBW)
Figure 2

Possible Endocrine modifications following an adverse intrauterine environment


.




                                                    ↓ 11 β HSD2
                                                    Gcort R


                                                    ↑ Glucocorticoids    +environment
    Adverse                                                              (diet,NO,hormones,
                                                    ↓ growth factors     fetal sex steroids)
    maternal
    environment                      Fetal growth
                                     GR+++ MR+       Fetus
    Malnutrition
    Stress Smoking
    Alcohol Drugs
    Disease Diabetes                                                   ↑ Glucocorticoids
    anemia
                     Fetal tissue programming
                     (vascular responses, HPA axis activity,           ↓ growth factors
                     insulin-glucose homeostasis, renal structure      (↓ IGF-I/II,↑IGFBP1)
                     ¿set point of GR ? PPAR-γ


    Genes+ environment
    (Obesity, smoking, OH,                               Adult disease
    salt, lack of excerise,stress)

				
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