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

References

1. Neel, J.V., Diabetes mellitus: a "thrifty" genotype rendered detrimental by

"progress"? Am J Hum Genet, 1962. 14: p. 353-62. 2. Ibanez, L., N. Potau, and F. de Zegher, Precocious pubarche, dyslipidemia, and

low IGF binding protein-1 in girls: relation to reduced prenatal growth. Pediatr Res, 1999. 46(3): p. 320-2.

3. Ibanez, L., et al., Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age. J Clin Endocrinol Metab, 1999. 84(12): p. 4739-41.

4. Hales, C.N. and D.J. Barker, Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia, 1992. 35(7): p. 595-601.

5. Barker, D.J., et al., Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Bmj, 1989. 298(6673): p. 564-7.

6. Mendonca, B.B., A.E. Billerbeck, and F. de Zegher, Nongenetic male pseudohermaphroditism and reduced prenatal growth. N Engl J Med, 2001. 345(15): p. 1135.

7. Woods, K.A., et al., The somatotropic axis in short children born small for gestational age: relation to insulin resistance. Pediatr Res, 2002. 51(1): p. 76-80.

8. Ibanez, L., et al., Early puberty: rapid progression and reduced final height in girls with low birth weight. Pediatrics, 2000. 106(5): p. E72.

9. Hales, C.N. and D.J. Barker, The thrifty phenotype hypothesis. Br Med Bull, 2001. 60: p. 5-20.

10. Barker, D.J., Fetal origins of coronary heart disease. British Medical Journal, 1995. 311(6998): p. 171-4.

11. Bateson, P., et al., Developmental plasticity and human health. Nature, 2004. 430(6998): p. 419-21.

12. Lueder, F.L., et al., Chronic maternal hypoxia retards fetal growth and increases glucose utilization of select fetal tissues in the rat. Metabolism, 1995. 44(4): p. 532-7.

13. Accili, D., et al., Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development. J Pediatr Endocrinol Metab, 1999. 12(4): p. 475-85.

14. Pessin, J.E. and A.R. Saltiel, Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest, 2000. 106(2): p. 165-9.

15. Cianfarani, S., D. Germani, and F. Branca, Low birthweight and adult insulin resistance: the "catch-up growth" hypothesis. Arch Dis Child Fetal Neonatal Ed, 1999. 81(1): p. F71-3.

16. Hattersley, A.T. and J.E. Tooke, The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet, 1999. 353(9166): p. 1789-92.

17. Stern, M.P., Strategies and prospects for finding insulin resistance genes. J Clin Invest, 2000. 106(3): p. 323-7.

18. Wertheimer, E., et al., Homozygous deletion of the human insulin receptor gene results in leprechaunism. Nat Genet, 1993. 5(1): p. 71-3.

19. Stoffers, D.A., et al., Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet, 1997. 15(1): p. 106-10.

20. Hattersley, A.T., et al., Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet, 1998. 19(3): p. 268-70.

21. Longo, N., et al., Activation of glucose transport by a natural mutation in the human insulin receptor. Proc Natl Acad Sci U S A, 1993. 90(1): p. 60-4.

22. Virkamaki, A., K. Ueki, and C.R. Kahn, Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest, 1999. 103(7): p. 931-43.

23. Nankervis, A., et al., Hyperinsulinaemia and insulin insensitivity: studies in subjects with insulinoma. Diabetologia, 1985. 28(7): p. 427-31.

24. Leibiger, B., et al., Short-term regulation of insulin gene transcription by glucose. Proc Natl Acad Sci U S A, 1998. 95(16): p. 9307-12.

25. Lew, A., W.J. Rutter, and G.C. Kennedy, Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ. Proc Natl Acad Sci U S A, 2000. 97(23): p. 12508-12.

26. Bennett, S.T., et al., Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet, 1995. 9(3): p. 284-92.

27. Dunger, D.B., et al., Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood [see comments]. Nat Genet, 1998. 19(1): p. 98-100.

28. Waterworth, D.M., et al., Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet, 1997. 349(9057): p. 986-90.

29. Bazaes, R.A., et al., Insulin gene VNTR genotype is associated with insulin sensitivity and secretion in infancy. Clin Endocrinol (Oxf), 2003. 59(5): p. 599-603.

30. Horikawa, Y., et al., Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet, 2000. 26(2): p. 163-75.

31. Gicquel, C., et al., Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet, 2005. 37(9): p. 1003-7.

32. Holness, M.J., Impact of early growth retardation on glucoregulatory control and insulin action in mature rats. Am J Physiol, 1996. 270(6 Pt 1): p. E946-54.

33. Holness, M.J. and M.C. Sugden, Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding. Am J Physiol, 1999. 276(1 Pt 1): p. E85-93.

34. Symonds, M.E., H. Budge, and T. Stephenson, Limitations of models used to examine the influence of nutrition during pregnancy and adult disease. Arch Dis Child, 2000. 83(3): p. 215-9.

35. Tapanainen, P.J., et al., Maternal hypoxia as a model for intrauterine growth retardation: effects on insulin-like growth factors and their binding proteins. Pediatr Res, 1994. 36(2): p. 152-8.

36. Wigglesworth, J.S., Fetal growth retardation. Animal model: uterine vessel ligation in the pregnant rat. Am J Pathol, 1974. 77(2): p. 347-50.

37. Jones, C.T., et al., Studies on the growth of the fetal sheep. Effects of surgical reduction in placental size, or experimental manipulation of uterine blood flow on plasma sulphation promoting activity and on the concentration of insulin-like growth factors I and II. J Dev Physiol, 1988. 10(2): p. 179-89.

38. Llanos, A.J., et al., Increased heart rate response to parasympathetic and beta adrenergic blockade in growth-retarded fetal lambs. Am J Obstet Gynecol, 1980. 136(6): p. 808-13.

39. Fukami, E., et al., Underexpression of neural cell adhesion molecule and neurotrophic factors in rat brain following thromboxane A(2)-induced intrauterine growth retardation. Early Hum Dev, 2000. 58(2): p. 101-10.

40. Gaziano, E., et al., The predictability of the small-for-gestational-age infant by real-time ultrasound-derived measurements combined with pulsed Doppler umbilical artery velocimetry. Am J Obstet Gynecol, 1988. 158(6 Pt 1): p. 1431-9.

41. Ogata, E.S., et al., Altered growth, hypoglycemia, hypoalaninemia, and ketonemia in the young rat: postnatal consequences of intrauterine growth retardation. Pediatr Res, 1985. 19(1): p. 32-7.

42. Ogata, E.S., M.E. Bussey, and S. Finley, Altered gas exchange, limited glucose and branched chain amino acids, and hypoinsulinism retard fetal growth in the rat. Metabolism, 1986. 35(10): p. 970-7.

43. De Prins, F.A. and F.A. Van Assche, Intrauterine growth retardation and development of endocrine pancreas in the experimental rat. Biol Neonate, 1982. 41(1-2): p. 16-21.

44. Garofano, A., P. Czernichow, and B. Breant, In utero undernutrition impairs rat beta-cell development. Diabetologia, 1997. 40(10): p. 1231-4.

45. Lueder, F.L. and E.S. Ogata, Uterine artery ligation in the maternal rat alters fetal tissue glucose utilization. Pediatr Res, 1990. 28(5): p. 464-8.

46. Economides, D.L., A. Proudler, and K.H. Nicolaides, Plasma insulin in appropriate- and small-for-gestational-age fetuses. Am J Obstet Gynecol, 1989. 160(5 Pt 1): p. 1091-4.

47. Sadiq, H.F., D.E. deMello, and S.U. Devaskar, The effect of intrauterine growth restriction upon fetal and postnatal hepatic glucose transporter and glucokinase proteins. Pediatr Res, 1998. 43(1): p. 91-100.

48. Jaquet, D., et al., Impaired regulation of glucose transporter 4 gene expression in insulin resistance associated with in utero undernutrition. J Clin Endocrinol Metab, 2001. 86(7): p. 3266-71.

49. Goland, R.S., et al., Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab, 1993. 77(5): p. 1174-9.

50. Phillips, D.I., et al., Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab, 1998. 83(3): p. 757-60.

51. Seckl, J.R., Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids, 1997. 62(1): p. 89-94.

52. McMillen, I.C., et al., Impact of restriction of placental and fetal growth on expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 messenger ribonucleic acid in the liver, kidney, and adrenal of the sheep fetus. Endocrinology, 2000. 141(2): p. 539-43.

53. Hotamisligil, G.S., et al., IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science, 1996. 271(5249): p. 665-8.

54. Day, C.P., et al., Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance. Diabetologia, 1998. 41(4): p. 430-4.

55. Maymon, E., et al., The tumor necrosis factor alpha and its soluble receptor profile in term and preterm parturition. Am J Obstet Gynecol, 1999. 181(5 Pt 1): p. 1142-8.

56. Hales, C.N., et al., Fetal and infant growth and impaired glucose tolerance at age 64. Bmj, 1991. 303(6809): p. 1019-22.

57. Barker, D.J., et al., Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 1993. 36(1): p. 62-7.

58. Fall, C.H., et al., Relation of infant feeding to adult serum cholesterol concentration and death from ischaemic heart disease. Bmj, 1992. 304(6830): p. 801-5.

59. Barker, D.J., et al., Fetal and placental size and risk of hypertension in adult life. Bmj, 1990. 301(6746): p. 259-62.

60. Stein, C.E., et al., Fetal growth and coronary heart disease in south India. Lancet, 1996. 348(9037): p. 1269-73.

61. Law, C.M., et al., Thinness at birth and glucose tolerance in seven-year-old children. Diabet Med, 1995. 12(1): p. 24-9.

62. Crowther, N.J., et al., Association between poor glucose tolerance and rapid post natal weight gain in seven-year-old children. Diabetologia, 1998. 41(10): p. 1163-7.

63. Eriksson, J.G., et al., Catch-up growth in childhood and death from coronary heart disease: longitudinal study. Bmj, 1999. 318(7181): p. 427-31.

64. Bavdekar, A., et al., Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both? Diabetes, 1999. 48(12): p. 2422-9.

65. Soto, N., et al., Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort. J Clin Endocrinol Metab, 2003. 88(8): p. 3645-50.

66. Colle, E., et al., Insulin responses during catch-up growth of infants who were small for gestational age. Pediatrics, 1976. 57(3): p. 363-71.

67. Crescenzo, R., et al., A role for suppressed thermogenesis favoring catch-up fat in the pathophysiology of catch-up growth. Diabetes, 2003. 52(5): p. 1090-7.

68. Cettour-Rose, P., et al., Redistribution of glucose from skeletal muscle to adipose tissue during catch-up fat: a link between catch-up growth and later metabolic syndrome. Diabetes, 2005. 54(3): p. 751-6.

69. King, H., R.E. Aubert, and W.H. Herman, Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care, 1998. 21(9): p. 1414-31.

70. Ong, K.K., et al., Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. Bmj, 2000. 320(7240): p. 967-71.

71. Reaven, G.M., The fourth musketeer--from Alexandre Dumas to Claude Bernard. Diabetologia, 1995. 38(1): p. 3-13.

72. Ong, K.K., et al., Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels. Diabetologia, 2004. 47(6): p. 1064-70.

73. Hofman, P.L., et al., Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab, 1997. 82(2): p. 402-6.

74. Eriksson, J.G., et al., Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals. Diabetologia, 2002. 45(3): p. 342-8.

75. Forsen, T., et al., The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med, 2000. 133(3): p. 176-82.

76. Bazaes, R.A., et al., Determinants of insulin sensitivity and secretion in very-low-birth-weight children. J Clin Endocrinol Metab, 2004. 89(3): p. 1267-72.

77. Hofman, P.L., et al., Premature birth and later insulin resistance. N Engl J Med, 2004. 351(21): p. 2179-86.

78. Kojima, M., et al., Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 1999. 402(6762): p. 656-60.

79. Howard, A.D., et al., A receptor in pituitary and hypothalamus that functions in growth hormone release. Science, 1996. 273(5277): p. 974-7.

80. Nakazato, M., et al., A role for ghrelin in the central regulation of feeding. Nature, 2001. 409(6817): p. 194-8.

81. Tschop, M., et al., Circulating ghrelin levels are decreased in human obesity. Diabetes, 2001. 50(4): p. 707-9.

82. Iniguez, G., et al., Fasting and post-glucose ghrelin levels in SGA infants: relationships with size and weight gain at one year of age. J Clin Endocrinol Metab, 2002. 87(12): p. 5830-3.

83. Jaquet, D., et al., Combined effects of genetic and environmental factors on insulin resistance associated with reduced fetal growth. Diabetes, 2002. 51(12): p. 3473-8.

84. Jaquet, D., et al., Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab, 2000. 85(4): p. 1401-6.

85. Petersen, K.F., et al., Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med, 2004. 350(7): p. 664-71.

86. Trayhurn, P. and I.S. Wood, Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr, 2004. 92(3): p. 347-55.

87. Ahima, R.S. and S.Y. Osei, Molecular regulation of eating behavior: new insights and prospects for therapeutic strategies. Trends Mol Med, 2001. 7(5): p. 205-13.

88. Maeda, K., et al., cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun, 1996. 221(2): p. 286-9.

89. Yamauchi, T., et al., Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature, 2003. 423(6941): p. 762-9.

90. Berg, A.H., et al., The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med, 2001. 7(8): p. 947-53.

91. Yamauchi, T., et al., The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med, 2001. 7(8): p. 941-6.

92. Yamamoto, Y., et al., Adiponectin, an adipocyte-derived protein, predicts future insulin resistance: two-year follow-up study in Japanese population. J Clin Endocrinol Metab, 2004. 89(1): p. 87-90.

93. Chandran, M., et al., Adiponectin: more than just another fat cell hormone? Diabetes Care, 2003. 26(8): p. 2442-50.

94. Kishida, K., et al., Disturbed secretion of mutant adiponectin associated with the metabolic syndrome. Biochem Biophys Res Commun, 2003. 306(1): p. 286-92.

95. Yu, J.G., et al., The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes, 2002. 51(10): p. 2968-74.

96. Lindsay, R.S., et al., Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet, 2002. 360(9326): p. 57-8.

97. Stefan, N., et al., Plasma adiponectin concentrations in children: relationships with obesity and insulinemia. J Clin Endocrinol Metab, 2002. 87(10): p. 4652-6.

98. Iniguez, G., et al., Adiponectin levels in the first two years of life in a prospective cohort: relations with weight gain, leptin levels and insulin sensitivity. J Clin Endocrinol Metab, 2004. 89(11): p. 5500-3.

99. Francois, I., M. van Helvoirt, and F. de Zegher, Male pseudohermaphroditism related to complications at conception, in early pregnancy or in prenatal growth. Horm Res, 1999. 51(2): p. 91-5.

100. Boisen, K.A., et al., Are male reproductive disorders a common entity? The testicular dysgenesis syndrome. Ann N Y Acad Sci, 2001. 948: p. 90-9.

101. Boisen, K.A., et al., Hypospadias in a cohort of 1072 Danish newborn boys: prevalence and relationship to placental weight, anthropometrical measurements at birth, and reproductive hormone levels at three months of age. J Clin Endocrinol Metab, 2005. 90(7): p. 4041-6.

102. Silver, H.K., et al., Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics, 1953. 12(4): p. 368-76.

103. Silfen, M.E., et al., Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity. J Clin Endocrinol Metab, 2002. 87(1): p. 398-403.

104. Saenger, P. and J. Dimartino-Nardi, Premature adrenarche. J Endocrinol Invest, 2001. 24(9): p. 724-33.

105. Ibanez, L., et al., Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche. J Clin Endocrinol Metab, 1999. 84(12): p. 4602-6.

106. Ibanez, L., et al., Polycystic ovary syndrome after precocious pubarche: ontogeny of the low-birthweight effect. Clin Endocrinol (Oxf), 2001. 55(5): p. 667-72.

107. Ibanez, L., et al., Hypersecretion of FSH in infant boys and girls born small for gestational age. J Clin Endocrinol Metab, 2002. 87(5): p. 1986-8.

108. Ibanez, L., N. Potau, and F. de Zegher, Ovarian hyporesponsiveness to follicle stimulating hormone in adolescent girls born small for gestational age. J Clin Endocrinol Metab, 2000. 85(7): p. 2624-6.

109. Ibanez, L., et al., Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational age: insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism. J Clin Endocrinol Metab, 2002. 87(12): p. 5702-5.

110. Jaquet, D., et al., Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women. J Clin Endocrinol Metab, 1999. 84(11): p. 3945-9.

111. Boonstra, V.H., et al., Serum dehydroepiandrosterone sulfate levels and pubarche in short children born small for gestational age before and during growth hormone treatment. J Clin Endocrinol Metab, 2004. 89(2): p. 712-7.

112. Hokken-Koelega, A.C., et al., Children born small for gestational age: do they catch up? Pediatr Res, 1995. 38(2): p. 267-71.

113. Boguszewski, M., et al., Hormonal status of short children born small for gestational age. Acta Paediatr Suppl, 1997. 423: p. 189-92.

114. de Waal, W.J., et al., Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone. Clin Endocrinol (Oxf), 1994. 41(5): p. 621-30.

115. Cutfield, W.S., et al., IGFs and Binding Proteins in Short Children with Intrauterine Growth Retardation. J Clin Endocrinol Metab, 2002. 87(1): p. 235-239.

116. Wilton, P., et al., Growth hormone treatment induces a dose-dependent catch-up growth in short children born small for gestational age: a summary of four clinical trials. Horm Res, 1997. 48 Suppl 1: p. 67-71.

117. de Zegher, F., et al., Growth hormone treatment of short children born small for gestational age: growth responses with continuous and discontinuous regimens over 6 years. J Clin Endocrinol Metab, 2000. 85(8): p. 2816-21.

118. Boguszewski, M.C., F. de Zegher, and K. Albertsson-Wikland, Serum leptin in short children born small for gestational age: dose-dependent effect of growth hormone treatment. Horm Res, 2000. 54(3): p. 120-5.

119. Chaussain, J.L., M. Colle, and J.P. Ducret, Adult height in children with prepubertal short stature secondary to intrauterine growth retardation. Acta Paediatr Suppl, 1994. 399: p. 72-3.

120. Lee, P.A., et al., International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics, 2003. 111(6 Pt 1): p. 1253-61.

121. Dahlgren, J. and K.A. Wikland, Final height in short children born small for gestational age treated with growth hormone. Pediatr Res, 2005. 57(2): p. 216-22.

122. Sas, T., et al., Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. J Clin Endocrinol Metab, 1999. 84(9): p. 3064-70.

123. Sas, T., P. Mulder, and A. Hokken-Koelega, Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH)

treatment in children with short stature born small for gestational age either with or without GH deficiency. J Clin Endocrinol Metab, 2000. 85(10): p. 3786-92.

124. Sas, T., et al., Carbohydrate metabolism during long-term growth hormone treatment in children with short stature born small for gestational age. Clin Endocrinol (Oxf), 2001. 54(2): p. 243-51.

125. van Erum, R., et al., Craniofacial growth in short children born small for gestational age: effect of growth hormone treatment. J Dent Res, 1997. 76(9): p. 1579-86.

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

.

Adverse maternal environmentMalnutritionStress SmokingAlcohol DrugsDisease Diabetesanemia

+environment(diet,NO,hormones,fetal sex steroids)

↓ 11 β HSD2Gcort R

↑ Glucocorticoids

↓ growth factors

Fetal growthGR+++ MR+

↑ Glucocorticoids

↓ growth factors(↓ IGF-I/II,↑IGFBP1)

Fetal tissue programming(vascular responses, HPA axis activity,insulin-glucose homeostasis, renal structure¿set point of GR ? PPAR-γ

Fetus

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

Adult disease