prenatal and postnatal growth and endocrine diseases francesco chiarelli
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Prenatal and Postnatal Growth and Endocrine Diseases
Francesco Chiarelli
Department of Pediatrics
University of Chieti, Italy
Francesco Chiarelli is Professor of Pediatrics and Pediatric Endocrinology at the Department of Pediatrics, University of Chieti, Italy
His field of research is diabetes mellitus in children, with reference to early detection and prevention of vascular complications
Professor Chiarelli published numerous papers on ranked international journals and has been invited as speaker at many meetings around the world
He has recently been appointed as both Chairman of ISPAD Scientific Committee (International Society for Pediatric and Adolescent Diabetes)(2002-2004) and Secretary General of ESPE (European Society for Paediatric Endocrinology)(2004-2007)
1. Definition and causes of IUGR
2. Growth and growth factors
3. Insulin-resistance
4. Adrenals
5. Gonads
1. Definition and causes of IUGR
2. Growth and growth factors
3. Insulin-resistance
4. Adrenals
5. Gonads
Pathological decrease of fetal growth
IUGR: definition
Birth weight < 2.5 Kg for gestational age of 37 weeks
Birth weight < 2SD below the mean value for gestational age
Birth weight < 10th (or 5th) percentile for gestational age
Definition of Small for Gestational Age (SGA)Birth weight and/or length of 2 or more standard deviations (SD) below the mean for gestational age and sex
IUGR and SGA newborns : Definition of clinical conditions at birth secondary to birth length (height) or birth weight according to gestational age
Birth Length
Below –2 SD Normal Greater than +2SD (IUGR or SGA)
Chatelain P, Endocrine Regulation 2000
Birth weight overweight overweight macrosomicgreater than +2SD IUGR1 “proportionate” (or SGA2) or “symmetrical”
Birth weight IUGR1 normal eutrophic
normal (or SGA2) or proportionate Birth weight proportionate SGA1 hypotrophic below -2 SD (“symmetrical”) or hypotrophic tall newborn (SGA2) SGA 2
1 IUGR is defined by birth length
2 SGA is defined by both birth length or birth weight
Boy, 5.2 years old. He is 95.3 cm tall and weighs 11.9 kg, which is
–4.2 SD score below the mean. His birth weight was
2,160 grams, which is –2.59 SD scores below the mean. His physical appearance is typical of SGA children showing a triangular-shaped face with a relatively large head and high forehead, a very lean body mass which is especially evident in his thinner than usual arms and legs.
Courtesy of Dr. Anita Hoekken-Koelega
What are the causes of SGA?Maternal• Vascular disease• Environmental
factors• Infection• Nutrition
Placental• Insufficiency• Abruption• Infarction• Vascular
abnormalities
Fetal• Genetic
abnormalities• Congenital
malformations• Metabolic
problems• Multiple
gestationsDemographic• Maternal age and
height• Father’s size• Obstetric history• Race
IUGR: phenotypes
Symmetrical IUGR (20-30%)• Proportionate reduction of all fetal mesurements• Aetiology: intrinsic alteration in growth potential or
severe nutritional deprivation overwhelming protective brain-sparing mechanism occuring prior to 26 weeks nd persisting until delivery
Asymmetrical IUGR (70-80%)• Disproportionate reduction of fetal mesurements due to
uteroplacental insufficiency with preferential shunting of blood to fetal brain
• High HC/AC FL/AC
IUGR: short-term consequencesIncreased perinatal morbidity and mortality
• 6-8 fold increase for intrapartum and neonatal death
• Respiratory distress• Necrotizing enterocolitis • Meconium aspiration• Electrolyte imbalance • Polycythemia• Intraventricular hemorrhage
IUGR: long-term consequences
• Short stature
• Cardiovascular disease
• Hypertension
• Metabolic disease (T2DM)
• Obesity
• Osteoporosis
1. Definition and causes of IUGR
2. Growth and growth factors
3. Insulin-resistance
4. Adrenals
5. Gonads
0
20 -
40 -
60 -
80 -
100 -
3 6 12 24
Hokken-Koelega A, Pediatr Res 1995
Pe
rce
nta
ge
(%)
Age (months)
Preterm Fullterm
Catch-up growth in IUGR
Postnatal growth in children born SGA
Karlberg J, Albertsson-Wikland K. Pediatr Res 1995;38:733–9.
The Concept of “CRITICAL WINDOW”T
rai t
Critical window
Time
Fetal life Infancy Adulthood
Welles J.C.K. J.Ther.Biol. 2003
PRENATALLY
insulin
IGF system switched-off
Poor maternal nutrition
Poor placental function
Low maternal fat stores
Nutrient demand > placental supply =
Fetal Undernutrition
Hormonal and metabolic adaptations in utero
GH IGF-1 Amino acid oxidation
Lactate oxidation
Glucose oxidation cortisol
Survival and development of vital organs (i.e brain)
Fetal programming IUGR
IGF-IIIGF-II
The regulation of fetal growth
Early gestationEarly gestation
IGF-I IGF-I
Late gestationLate gestation InsulinInsulin
IGFBP-1IGFBP-1
IGFBP-3IGFBP-3
GH GH
Glucose and amino acid availability
Glucose and amino acid availability
GH-IGF axis HypothalamusGHRH
Ghrelin
Somatostatin
IGF-1
Liver
Pituitary Stomach
GH receptor
-
-
GH
+ -
GHBP
IGF-1
IGFBP and ALS
+
+
IGF receptor
Target tissues
Endocrine
Autocrine
Paracrine
+
+
+
Trends Endocrinol Metab, 2002
Normal glucose and amino acid availability
Normal glucose and amino acid availability
GHGH IGF-IIGF-I InsulinInsulin
IGFBP-1IGFBP-1
The regulation of fetal growth
IGFBP-3IGFBP-3
GROWTH GROWTH
Normal glucose transport in muscle and brain
Normal glucose transport in muscle and brain
Reduced glucose and amino acid availability Reduced glucose and amino acid availability
GHGH GHGH IGF-IIGF-I IGF-IIGF-I InsulinInsulin InsulinInsulin
IGFBP-1 IGFBP-1 IGFBP-3 IGFBP-3
IUGR IUGR
Fetal salvage hypothesis
Reduced glucose transport in muscle and normal in brainReduced glucose transport in muscle and normal in brain
0
50
100
150
Simmons R, Pediatr Res 1992IUGR
Control
Brain tissue
Glial cells Lung tissue
FibroblastsType II
Glu
cose
tra
nsp
ort
% Fetal salvage hypothesis
Maternal glucose concentration
Glucose sensing by fetal pancreas
Insulin secretionby fetal pancreas
Insulin-mediated growth of fetus
Birthweight
Fetal genetics
Fetal insulin resistance
Fetal insulin hypothesis
Glucose challenge in fetuses
0
5
10
0 1 3 5 10 15 20
0
10
20
30
0 1 3 5 10 15 20 Time (min)
Glu
co
se
(m
mo
l/L)
Insu
lin m
U/L
)
Nicolini U, Horm Metab Res 1990
IUGR
Control
Hormone levels in fetuses
0
500
1000
0
10
20
30
40
0
100
200
300
400
IGF-I (mcg/L) IGFBP-3 (mcg/L)
IGFBP-1 (mcg/L) Insulin (mcU/ml)
IUGRControl Langford KS, J Clin Endocrinol Metab 1994
0
4
8
Reprogramming of the GH-IGF axis in IUGR HypothalamusGHRH
Ghrelin
Somatostatin
IGF-1
Liver
Pituitary Stomach
GH receptor
-
-
GH
+ -
GHBP
IGF-1
IGFBP-1
+
+
IGF receptor
Target tissues
+
-
-+
Enhanced negativefeedback
Hepatic GHresistance
Alterated target tissueGH resistance
IGF resistance
Insulin
-
+
+
Trends Endocrinol Metab, 2002
POSTNATALLY
Adequate Nutrient Supply
insulin production
IGF system switched-on
Catch-up Growth
Insulin Insulin ResistanceResistance
GH GH ResistanceResistance A. Mohn, F. Chiarelli, mod., 2002
Insulin like action+
IGFBP-3 fragment
0
10
20
30
40
50
60
70
80
90
100
0 60 90 120 150 180 210
0
5
10
15
20
25
0 60 90 120 150 180 210
Kalhan SC, Pediatr Res 1995
Control
IUGR
Glucose infusion (2.6-4.6 mg/kg/min)
Glu
co
se
mg
/dl
Insu
lin m
U/L
Glucose challenge in newborn
Time (min)
Hormone levels in newborns
0
500
1000
0
20
40
60
80
0
100
200
300
0
10
20
30
IGF-I (mcg/L) IGFBP-3 (mcg/L)
IGFBP-1 (mcg/L) GH (mcg/L)
IUGR de Zegher F, Acta Paediatr 1997
00,5
11,5
22,5
33,5
4
Insulin (mU/L)
Control
Hormone levels in IUGR from birth to 24 mo of age
1
12
24
6
4644 32 21 1.2 0.9
85 36
1.5 0.4
Leger J, Pediatr Res 2001
0
Time (months) GH IGF-1 IGFBP-3
19 9
IUGR
Control
IUGR
Control128108
79339035
1.80.51.70.7
6.13.5 81 37 2.3 0.7IUGRControl 3.42.
410236 2.10.6
Control 2.72.2 7335 2.10.4
3.84.2 89 34 2.6 0.8
IUGR
2.62.5 98 44 2.7 0.6IUGRControl 2.21.
68029 2.60.6
Values are mean SD
Hormone levels in IUGR with and without catch-up growth
1
12
24
6
6390 28 18 1.2 1.6
31 21
1.1 0.9
Leger J, Pediatr Res 2001
0
Time (months) GH IGF-1 IGFBP-3
4843
< - 2 SDS
> - 2 SDS
157
1511
80267434
1.40.21.80.5
42 75 41 1.9 0.5< - 2 SDS> - 2 SDS 710 81 36 2.30.7
> - 2 SDS 44 8935
2.70.8
43 74 26 2.3 0.3 < - 2 SDS
33 50 18 2.2 0.5< - 2 SDS
> - 2 SDS 33 10143 2.80.6
Values are mean SD
< - 2 SDS
> - 2 SDS
Hormone levels in infants
0
1
2
3
0
20
40
60
IGF-I (mcg/L) IGFBP-3 (mcg/L)IGFBP-1 (mcg/L)
IUGRControl Woods KA, Pediatr Res 2002
Insulin (mU/L)
0
10
20
30
0
50
100
150
0
100
200
300
Insulin sensitivity
0
50
100
150
Beta cell function
Maternal glucose concentration
Glucose sensing by fetal pancreas
Insulin secretionby fetal pancreas
Insulin-mediated growth of fetus
Birthweight Birthweight
Fetal genetics(IGF-1,GK,insulin, etc.)Fetal genetics(IGF-1,GK,insulin, etc.)
Fetal insulin resistanceFetal insulin resistance
Fetal insulin hypothesis
Overnight GH secretion in infancy
GH (mUI/l)IUGR group
(n=13)
Control group
(n= 15)
p value
(t test)
Maximum
Minimum
No. of pulses
Pulse amplitude
Mean
Area under curve
55.9 (30.4-80.5)
13.1 (7.2 –19.1)
39.6 (15.6-75.9) 0.1
8.9 (3.7-18.5) 0.004
1.2 (<0.4-2.1) 0.6 (0.5-1.3) 0.004
5.4 (3-7) 4.3 (3-8) 0.02
115.8 (62-171.1) 84.1 (28.7-165.8) 0.02
25.2 (17.4-36.7) 20.6 (9.1-40.8) 0.12
Values are mean and range
Woods KA, Mohn A, Pediatr Res 2002