prenatal and postnatal growth and endocrine diseases

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Prenatal and Postnatal Growth and Endocrine Diseases Francesco Chiarelli Department of Pediatrics University of Chieti, Italy

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Page 1: Prenatal and Postnatal Growth and Endocrine Diseases

Prenatal and Postnatal Growth and Endocrine Diseases

Francesco Chiarelli

Department of Pediatrics

University of Chieti, Italy

Page 2: Prenatal and Postnatal Growth and Endocrine Diseases

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)

Page 3: Prenatal and Postnatal Growth and Endocrine Diseases

1. Definition and causes of IUGR

2. Growth and growth factors

3. Insulin-resistance

4. Adrenals

5. Gonads

Page 4: Prenatal and Postnatal Growth and Endocrine Diseases

1. Definition and causes of IUGR

2. Growth and growth factors

3. Insulin-resistance

4. Adrenals

5. Gonads

Page 5: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 6: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 7: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 8: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 9: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 10: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 11: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 12: Prenatal and Postnatal Growth and Endocrine Diseases

IUGR: long-term consequences

• Short stature

• Cardiovascular disease

• Hypertension

• Metabolic disease (T2DM)

• Obesity

• Osteoporosis

Page 13: Prenatal and Postnatal Growth and Endocrine Diseases

1. Definition and causes of IUGR

2. Growth and growth factors

3. Insulin-resistance

4. Adrenals

5. Gonads

Page 14: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 15: Prenatal and Postnatal Growth and Endocrine Diseases

Postnatal growth in children born SGA

Karlberg J, Albertsson-Wikland K. Pediatr Res 1995;38:733–9.

Page 16: Prenatal and Postnatal Growth and Endocrine Diseases

The Concept of “CRITICAL WINDOW”T

rai t

Critical window

Time

Fetal life Infancy Adulthood

Welles J.C.K. J.Ther.Biol. 2003

Page 17: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 18: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 19: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 20: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 21: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 22: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 23: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 24: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 25: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 26: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 27: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 28: Prenatal and Postnatal Growth and Endocrine Diseases

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)

Page 29: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 30: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 31: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 32: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 33: Prenatal and Postnatal Growth and Endocrine Diseases

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

Page 34: Prenatal and Postnatal Growth and Endocrine Diseases

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