1. 1. Definition and causes of IUGR 2. Growth and growth factors 3. Insulin-resistance 4. Adrenals 5. Gonads

2. Time (mins) Glycemia (mmol/L) Insulin Resistance in IUGR IUGRControl Hofman P, J Clin Endocrol Metab 1997 Insulinemia (mcU/L) 1020504030 90 807060 10205030 90

3. Insulin Resistance in IUGR IUGR Number 19 18 Sex (Female/Male) 10/9 10/8 BMI 17.6 ± 1.1 17.8 ± 1.3 Height SDS -2.7 ± 0.73 -2.5 ± 0.68 Midparental SDS -0.8 ± 0.7 -0.7 ± 0.6 Birth weight SDS -2.81 ± 0.92 -0.30 ± 0.69 Gestational Age (weeks) 36.9 ±1.9 37.3 ± 2.0 Age (1 st evaluation, range, years) 8.4 - 10.3 8.1 - 10.6 Age (2 st evaluation, range, years) 13.4 - 14.6 13.5 - 14.8 Chiarelli F, Mohn A, Acta Paediatr 1999 Controls

4. Insulin Resistance in IUGR Prepubertal Pubertal Insulin peak after tolbutamide (mU/l) 96.5±11.454.7±7.2 108±13.162.3±7.4 Blood glucose peak (mmol/L) 11.4±0.58.7± 0.3 12.2±0.6 9.6±0.3 97.2±11.568.2±12.6 IUGR 36.9±6.148.1±8.9 Insulin peak after glucose (mU/l) Control Chiarelli F, Mohn A, Acta Paediatr 1999

5. Insulin Sensitivity and β-cell capacity in prepubertal children born SGA 16.2±3.3 SGA Lowest tertile Δ BMI 2-9 yrs Veening MA, ESPE 2003 (P2-540) Diabetes 52: 1756-1760, 2003 M-value AGA Tertiles of Δ BMI 2-9 years: M-value (mg/kg.min), FIR and SIR (mmol/l.min) Middle tertile Δ BMI 2-9 yrs Highest tertile Δ BMI 2-9 yrs 14.8±0.3 14.3±2.9 AGA 16.3±3.3 11.6±1.6 11.1±3.9 2.3±1.01.8±0.830.7±7.321.8±6.5 SGA FIRSIR 2.9±0.9 2.3±0.7 2.5±0.5 2.0±1.132.0±10.535.8±9.1 39.5±8.0 45.0±14.4 AGA: 1 st vs 3 rd tertile; ns SGA: 1 st vs 3 rd tertile; M-values: p= 0.012; FIR: p= 0.025; SIR: p= 0.004 M-value – hyperinsulinemic euglycemic clamp FIR and SIR – hyperglycemic clamp and arginine infusion

6. Impaired Insulin-Stimulated Muscle Glucose Uptake in Young Adults with Low Birth Weight Hermann TS et al., J Clin Endocrinol Metab 2003 p<0.04

7. Insulin peak after Tolbutamide (mU/l) 96.5±11.4 54.7±7.2 108±13.1 62.3±7.4 Blood glucose peak (mmol/L) 11.4±0.58.7± 0.312.2±0.69.6±0.3 97.2±11.5 Insulin Resistance in IUGR throughout Puberty 68.2±12.6 IUGR 36.9±6.148.1±8.9 Insulin peak after glucose (mU/l) Mohn A, Chiarelli F, submitted, 2004 Prepubertal Pubertal Control IUGR Control Postpubertal 93.5±10.241.0±6.8 98.7±10.3 59.1±5.2 11.6±0.49.1±0.4

8. Pro12Pro (n) 84 (56) Mean Fasting Insulin Concentration and HOMA-IR Index According to PPAR-γ gene polymorphism and birthweight Fasting insulin (pmol l -1 ) Eriksson JG et al., Diabetes 2002 Birthweight (g) -3000P-3500>3500 Pro12Ala/Ala12Ala (n) P 71 (161) 65 (107) 60 (37)60 (67)65 (48) 0.008 0.020.99 0.003 0.31

9. 34.9 Size at Birth and at 7 Years by INS VNTR genotype in ALSPAC Children Head circumference at birth (cm) Mean n INS VNTR genotype I/IIII/IIII/III Birth weight (g) Mean n Head circumference at 7 yrs (cm) Mean n BMI at 7 years (kg/m 2 ) Mean n Weight at 7 years Mean n Waist circumference at 7 yrs (cm) Mean n 34.9 35.3 50346892 3,4953,4893,552 575528107 52.5 52.9 575528107 25.425.3 26.3 527573 16.1 16.5 573527107 56.456.3 57.3 573528107 P < 0.005P < 0.05 Ong KK et al., Diabetes 2004

10. Ponderal Index at Birth; Body-Mass Index at the Age of 2 Years, 12 Years, and Currently; and Prevalence of Impaired Glucose Tolerance or Diabetes, According to the Age at the Time of Adiposity Rebound 233 2-5 Yr Bhargava SK, Sachdev HS, et al., N Engl J Med 350: 865-875, 2004 (mod.) Age at Adiposity Rebound No of Subjects Ponderal Index at Birth Body-Mass Index at 2 yr Body-Mass Index at 12 yr Current Body-Mass Index IGT or Diabetes (%) 6 Yr 7 Yr 8-9 Yr All subjects P value 252 363 395 1243 – 24.5 24.9 24.6 25.0 24.8 0.06 15.2 15.7 15.8 15.6 <0.001 16.8 16.1 15.7 15.0 15.7 <0.001 26.0 25.7 24.7 23.4 24.8 21.0 13.9 14.6 12.2 14.9 0.006

11. Poor maternal nutrition and/or poor placental function Fetal undernutrition Programming of glucose-insulin metabolism Non diabetic Type 2 diabetic Ozanne S.E, Hales C.N. Trends Endocrinol Metab 2002 Poor postnatal nutrition High energy expenditure Thin adult Energy excess Obese adult

12. Dutch-SGA study: Growth response

13. Insulin (mU/l) 3.88.913.9 5.2 Insulin sensitivity 1 26.9 8.84.017.6 Glucose tolerance 2 2.62 2.19 2.392.49 79.2 Glucose and insulin levels in IUGR children 66.6 baseline 1 yr2 yrPost-GH 79.273.8 Glucose (mg/dl) 1 Bergman minimal model 2 Slope of glucose decline 10-40 min post IVGTT de Zegher F, J Clin Endocrinol Metab 2002

14. Cutfield WS et al., J Pediatr 142:113; 2003 Reduced Insulin Sensitivity during GH therapy in children born SGA N: 12 SGA Age: 9.3  1.0 ys r-hGH: 0,7 IU/Kg/w

15. 1. Definition and causes of IUGR 2. Growth and growth factors 3. Insulin-resistance 4. Adrenals 5. Gonads

16. Fetal programming Mother Placenta Fetus Stress (e.g. undernutrition) Cortisol

17. ACTH, cortisol, and DHEAS concentration in IUGR fetuses Umbilical cord plasma level Normally grown fetuses CRH>200pmol/L CRH <200 pmol/L ACTH (pmol/L) Cortisol (nmol/L) DHEAS ( mmol/L) (n=21)(n=7) (n=28) 3.3 ± 0.7 7.0 ± 2.2 200 ± 50 b 5.3 ± 1.3 a 437± 100 a 7.7 ± 0.66.1 ± 0.6 b 2.3 ± 0.7 a 220 ±40 Growth-retarded Fetuses a p < 0.01 GRF vs NGF b p < 0.01 within IUGR Goland et al., J Clin Endocrinol Metab 1993

18. <5.5- 6.5- 7.5- 8.5- 9.5>9.5 300 - 350 - 400 - 450 - Mean fasting plasma cortisol concentration and birth-weight Birthweight (lbs) Fasting plasma cortisol (nmol) Phillips et al., J Clinical Endocrinol Metab, 1998

19. 1. Definition and causes of IUGR 2. Growth and growth factors 3. Insulin-resistance 4. Adrenals 5. Gonads

20. Francois I, et al. Pediatr Res 42: 899-901 1997 Low Birth Weight & Subsequent Male Subfertility SDS Birth Weight Normal n= 128 Unexplained Subfertility n= 32 p=0.012 Subfertility (n= 60): abnormal semen analysis

21. LH and FSH Hypersecretion and Reduced Uterine and Ovarian Size in Young Women Born SGA Ibanez L et al., Hum Reprod 2003 IU/L cm 2 cm 3 LH FSH Uterine AreaMean Ovarian Volume p = 0.01 p = 0.005 p < 0.0001 n=27n=20

22. Manifestations of PCOS at different ages In utero Peripuberty Adolescence / adulthood Ageing Small baby syndrome  IUGR Exaggerated adrenarche  Increased levels of: - Adrenal androgens - Insulin  Functional ovarian hyperandrogenism Polycystic ovary syndrome  Anovulation  Polycystic ovaries  Obesity (50%) Metabolic syndrome  Diabetes  Hypertension  Dyslipidaemia  Increased plasminogen activator inhibitor-1 Long-term health effects Leads to Precocious puberty Reproductive disorder Metabolic effects

23. Ibanez L et al., J Clin Endocrinol Metab 1998 Precocius pubarche - + + + Ovarian hyperandrogenism - - + + Insulin resistance - - - + n=31 n=25 n=12 n=11  Std Dev.  Std Err. Mean * p=0.01 * * * Birth weight of postmenarcheal girls with or without a history of precocious adrenarche Birthweight SDS

24. Gonadal Function in Male Born SGA Age range: 15.2 – 20.8 Inhibin B (pg/mL) p<0.0001 Vs. * Cicognani A et al., J Pediatr 2003

25. Reduced Ovulation Rate in Adolescent Girls Born SGA Mean age: 15.5 yr, >3 yr post-menarche Ibanez L et al., J Clin Endocrinol Metab 2002 Ovulations detected over 3 months Mean AGA SGA Birthweight (Kg) 3.3 2.3 FSH (U/L) 4.0 6.7 Insulin (mU/L) 8.3 13.0 DHEAS (mcg/dL) 157 257

26. Future perspectives Children born with IUGR Adults born with IUGR Establish whether GH therapy worsens insulin resistance and increases risks for NIDDM and cardiovascular disease later on in life. Develop strategies in order to reduce the inborn risk of NIDDM and cardiovascular disease.

27. The Economist DECEMBER 13TH-19TH 2003 www.economist.com