1. Obesity and reproduction Professor Aleksandar Ljubić Medical school University of Belgrade Clinic for Obstetrics and Gynecology Clinical center of Serbia

2. Obesity and reproduction Epidemiology Patophysiology IVFPregnancy Intergenerational obesity

3. Health Challenges of the Future?   Increasing burden of “lifestyle” diseases 1. Obesity 2. Cardiovascular disease (hypertension, atherosclerosis) 3. Type 2 Diabetes   Associated with increasing morbidity and mortality   Appearing at younger and younger ages WHO, 2005

4. Obesity – pandemic disease WHO, 2005

5. Women of reproductive age Martorell, R, et al; Eur J Clin Nutrit, 2000

6. Obesity and its associated metabolic problems are appearing at younger ages WHO, 2005

7. Horgan, Bellizzi and Dietz, 2000. IOTF. Obesity during childhood in developing countries

8. Cover page of The Economist, December 13-19th, 2003. Our physiology has not been able to adapt to advances in technology and food production.

9. Chrousos GP 2009

10. PCOS and obesity   PCOS   the most frequent ovarian disorder in premenopausal women   Azziz et al., 2004   Obesity   20–69% of women with PCOS - BMI > 30   Independent of obesity, women with PCOS have increased intra-abdominal fat accumulation   Asuncion et al., 2000; Azziz et al., 2004; Carmina et al., 2007.

11.   NIH PCOS groups   a more severe phenotype   ESHRE including ovulatory and non- hyperandrogenic PCOS groups   less severe with metabolic features primarily related to excess weight, specifically increased abdominal fat   Moran and Teede, 2009. PCOS clasification

12. PCOS and long-term sequelae   IR and subsequent hyperinsulinaemia:   Impaired glucose tolerance,   Gestational diabetes mellitus - OR 2.94,   T2DM   Cardiovascular disease   exacerbated by coexistent obesity   Boudreaux et al., 2006   Ehrmann et al., 2006

13. Abdominal adiposity and PCOS Escobar-Morreale H et al. Trends in Endocrinology and Metabolism, 2007; 18(7): 266-272.

14. PCOS and obesity - patophysiology   Compensatory hyperinsulinaemia - significant contributor to the hyperandrogenism   Increased serum insulin   stimulates ovarian androgen production,   reduces SHBG   increasing serum levels of free bio-available androgens   Apart from reproductive (anovulation) and cosmetic (acne, alopecia, hirsutism) consequences hyperandrogenaemia   increases abdominal obesity,   aggravates existing IR   Preadipocytes have androgen receptors   and high androgen levels have been shown to induce selective IR in cultured adipocytes D. Rachon, H. Teede Molecular and Cellular Endocrinology (2010)

15.   Molecules secreted by the intraabdominal adipose tissue (adipokines)   promote ovarian androgen production.   TNF stimulate proliferation and steroidogenesis apoptosis and anovulation in the rat’s ovary   leptin induces anovulation by direct ovarian effects   Duggal et al., 2000   Intraabdominal fat tissue   express enzymes involved in the metabolism of androgens   further contribute to the hyperandrogenism in women with PCOS   Gambineri et al., 2002 PCOS and obesity - patophysiology

16.   IR and ovarian hyperandrogenism   promote the accumulation of intra- abdominal fat   primary determinants of the metabolic abnormalities present in women with PCOS D. Rachon, H. Teede Molecular and Cellular Endocrinology (2010) PCOS and obesity - patophysiology

17. Fat distribution and anovulation   Abdominal fat in anovulatory women - SAF not intraabdominal fat.   Abdominal and trunk SAF accumulation are associated with anovulation. Kuchenbecker et al, J Clin Endocrinol Metab 2010

18. PCOS – abdominal adiposity Escobar-Morreale H et al. Trends in Endocrinology and Metabolism, 2007;18 (7) : 266-272.

19. Obesity - sterility   Multiple steroid and metabolic disturbances   Production and effect of   Insulin, leptin, resistin, ghrelin and adiponectin. Poretsky et al., 1999; Moschos et al., 2002; Tanbo, 2002; Pasquali et al., 2003),

20. Ghrelin reproductive function Garcia MC et al, Reproduction 2007; 133: 531-540 A putative signal for energy insufficiency Follicle growth and maturation Embryonic development Implantation

21. Fedorscak et al, Human Reproduction, 2004 No - 5019 Obesity and IVF

22. Fedorscak et al, Human Reproduction, 2004 Obesity and IVF

23. BMI – age - IVF Response BMI UnderwtNormalOverwtObese Can. Cy. (%) 28.618.820.617.6 Ret. Oocytes 15.514.113.414.5 Mat. Oocytes 11.810.49.910.7 Fert. Oocytes 9.38.68.48.5 Sneed et al. Sneed et al. Human Reproduction 2008

24. Outcome BMI UnderwtNormalOverwtObese Pts with ET 20498258253 Em. Trans. 2.22.32.32.3 Imp. Rate (%) 27.523.323.421.5 Preg. Rate (%) 58.848.745.339.5 Misc. Rate (%) 017.715.110.0 Clin.Preg. (%) 58.838.636.835.1 BMI – age - IVF

25. Sneed et al. Sneed et al. Human Reproduction 2008 Younger patients - BMI reduction BMI – age - IVF

26. Outcome measures   The primary outcome measure was live birth rate per woman.   Secondary outcome measures included   total dose of gonadotrophins,   Cancellation rates,   number of oocytes retrieved,   number of embryos obtained,   pregnancy rate,   miscarriage rate and   ovarian hyperstimulation syndrome (OHSS) rate. A. Maheshwari, Aberdeen, Human Reproduction Update, 2007, 1843 studies

27. Live birth rate   In women with BMI of 25.   In women with BMI of 30.   There was significant statistical heterogeneity in results from the different studies (P = 0.003). A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

28. Pregnancy rate   BMI of 25.   Significant statistical heterogeneity (P = 0.03). A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

29. Pregnancy rate   BMI 20–25, OR - 1.40 (95% CI: 1.22, 1.60) as compared to a BMI > 25.   Significant statistical heterogeneity (P< 0.00001). A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

30. Pregnancy rate   BMI 30.   Significant statistical heterogeneity (P< 0.00001). A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

31. The dose of gonadotrophins   The dose of gonadotrophins was higher in women with BMI of > 25 (WMD 210.08, 95% CI: 149.12, 271.05) in comparison with those with BMI of < 25. A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

32. The dose of gonadotrophins   The requirement for gonadotrophins was higher (WMD 361.94, 95% CI: 156.47, 567.40) in obese women (BMI > 30 versus BMI < 30) A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

33. Number of oocytes retrieved   The WMD of the number of oocytes recovered in women with BMI 25. A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

34. Number of oocytes retrieved   The WMD of the number of oocytes retrieved in women with BMI 30. A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

35. Cancellation rate   BMI of > 25 OR were 1.83 (95% CI: 1.36, 2.45), as compared to BMI < 25.   BMI of > 30, OR were 1.59 (95%CI: 0.53, 4.80), as compared to women with BMI < 30   Significant statistical heterogeneity (P = 0.05). A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

36. Ovarian hyperstimulation rate   BMI of > 25, the odds of OHSS were 1.12 (95% CI: 0.74, 1.68), as compared to BMI of < 25.   BMI of > 30, the odds of OHSS were 1.16 (95% CI: 0.69, 1.96), as compared to BMI of < 30. A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

37. Miscarriage rate   BMI of > 25, the odds were 1.33 (95% CI: 1.06, 1.638), compared to BMI of < 25.   The results showed statistical heterogeneity (P = 0.05). A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

38. Miscarriage rate   The risk of miscarriage was higher (OR = 1.53, 95% CI: 1.27, 1.84), in women with BMI > 30 versus BMI < 30.

39.   Increased FSH consumption   Less oocytes   Lower E2   More cancelation   Less pregnancies Crosignani et al., 1994; Homburg et al., 1996; Soderstrom-Anttila et al., 1996; Wang et al., 2000; Wittemer et al., 2000; Carrell et al., 2001; Loveland et al., 2001; Mulders et al., 2003; Nichols et al., 2003 Obesity and IVF

41. Pregnancy complications - BMI Adapted from Galtier-Dereure et al. (1995)

42. Congenital malformations – BMI Watkins ML, et al., Pediatrics 111:1152, 2003)

43. Why might obesity lead to congenital anomalies?  Four potential mechanisms: - Undiagnosed diabetes Hypertension Dyslipidaemia Glucose intolerance Inflammation Abdominal Obesity

44. Why might obesity lead to congenital anomalies?  Four potential mechanisms:  Undiagnosed diabetes  Folate status

45. Why might obesity lead to congenital anomalies?  Four potential mechanisms:  Undiagnosed diabetes  Folate status  Nutritional deficiencies

46. Why might obesity lead to congenital anomalies?  Four potential mechanisms:  Undiagnosed diabetes  Folate status  Nutritional deficiencies  Difficulties with antenatal detection

47. The Developmental Origins of Health and Disease   “A process whereby a stimulus or insult applied at a critical or sensitive period of development results in long term or permanent changes in the structure or function of the organism” Lucas J. The childhood environment and adult, 1991

51. Parsons et al, BMJ 2001 Excessive birth weight

53. Fetal programming   Increased weight gain   Glucose intolerance   Insulin resistance   Diabetes   Cardiovascular problems

55. Prevention / Treatment   Influence of maternal and fetal health on Obesity pandemic   When to intervene?   Before conception   Around conception   During pregnancy   During childhood

56. Inter-generational obesity cycle

57. “Maternal obesity Next preventable risk for reducing perinatal mortality and morbidity” CNATTINGIUS, S ET AL; NEJM, 1998