Tom Tanbo Section for Reproductive medicine, Department of Gynecology

1. Obesity and reproduction Fertility and early pregnancy outcome in overweight and obesity Tom Tanbo Section for Reproductive medicine, Department of Gynecology Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway

2. Venus of Willendorf is an 11 cm (4.3 in) high statuette of a female figure estimated to have been made between 22,000 and 21,000 BCE. It was discovered in 1908 by archaeologistJosef Szombathy at a paleolithic site near Willendorf, a village in Lower Austria near the city of Krems The apparent large size of the breasts and abdomen, and the detail put into the vulva, have led scholars to interpret the figure as a fertility symbol

3. On Airs, Waters, And PlacesbyHippocrates ”…..but on that of the women, they are embonpoint and humidity; for the womb cannot take in the semen, nor is the menstrual discharge such as it should be, but scanty and at too long intervals; and the mouth of the womb is shut up by fat and does not admit the semen; and, moreover, they themselves are indolent and fat, and their bellies cold and soft. From these causes the Scythian race is not prolific. Their female servants furnish a strong proof of this; for they no sooner have connection with a man than they prove with child, owing to their active course of life and the slenderness of body.”

4. ”Critical weight hypothesis”Frisch et al. Science 1970 Menarche occurs at a critical level of fat mass corresponding to 17% of total body weight Obese pre-pubertal girls enter menarche earlier than normal weight girls To maintain ovulatory cycles, a minimum of 22% fat mass of total body weight is required

5. The minimum weight necessary for a particular height for onset of menstrual cycles as indicated on the weight scale by the 10th percentile (height growth must be completed or approaching completion) Frisch RE. Hum Reprod 1987

6. The relationship between mean BMI z - scores and Tanner staging of breast development in 7- to 12-year-old girls.Kaplowitz, P. B. Pediatrics 2008 Z = x – μ/σ

7. The minimal weight necessary for a particular height for restauration of menstrual cycles is indicated on the weight scale by the 10th percentile Frisch RE. Hum Reprod 1987

8. Multivariate odds ratios with 95% CI of ovulatory disorder infertility by BMI and distribution of BMI Nurses’ Health Study II, 1989–1995. Rich-Edwards et al. Epidemiol 2002

9. BMI in relation to time to spontaneous ongoing pregnancy within 12 months in subfertile, ovulatory womenvan der Steeg, JW. Hum. Reprod. 2008

10. Weight extremes and anovulatory infertility Underweight/starvation Hypogonadotrophic hypogonadism Overweight/obesity PCOS

11. ART pregnancy rate in normal weight compared with overweight and obese Maheshwari Hum Reprod Update 2007

12. Obesity and OR of miscarriage regardless of the method of conception (general population) Metwally et al Fertil Steril 2007

13. Live birth rate data for different BMI categories Rittenberg V. RBM Online 2011

14. Miscarriage rate data for different BMI categories Rittenberg V. RBM Online 2011

15. Surrogate obesity negatively impacts pregnancy rates in third party reproduction DeUgarte Fertil Steril 2010 Analysis with BMI as a continous variable showed a reduction in implantation rate by a factor of 0.98 for each unit increase in BMI

16. Known actions of adipokines in human fertility and trophoblast development Tersigni C. Obstet Gynecol Survey 2011

17. Leptin • Discovered 1994 • Satiety factor • Synthesized in white fat tissue • Synthesis stimulated by increase in blood glucose and insulin levels • Increased leptin level increase metabolic activity and reduce food intake • Overweight subjects are resistant to leptin

18. Serum leptin level as a function of fat mass Considine RV. N Engl J Med 1996

19. Leptin stimulates hypothalamic secretion of GnRH

20. 24 hours profile at 7 min. intervals of leptin, LH og estradiol Licinio J. PNAS 1998

21. Correction of the sterility defect in homozygous ob/ob female mice by treatment with the human recombinant leptin Chebab FF. NatureGenetics 1996

22. Human leptin system interactions at the maternal-embryonic interphase during the preimplantation and implantation phases Cervero A. JCEM 2004

23. DNA fragmentation in day 5 mouse blastocysts exposed to leptinFedorcsak et al, Biol Reprod 2003

24. hCG on Day 16 after ovulation induction in successful IVF pregnancies Eskild A. et al. submitted

25. Correlation between obesity, infertility and androgen levels

26. PCOS • Hyperandrogenism • Anovulation • Polycystic ovaries

27. PCOS and insulin resistance

28. Two cell - two gonadotropin theory Clinical signs (hirsutism, acne, male hair loss) + Insulin - Hyperandrogenism Adiponectin Follicular atresia Anovulatory infertility

29. Endocrine and clinical effects of obesity and insulin resistance Ramsay, J. E et al. BMJ 2006

30. Ovulation induction in PCOS • Weight loss by life style modification • Clomiphene citrate • Metformin • Gonadotropins • Electrocautery of the ovaries • IVF

31. Efficacy of lifestyle intervention in anovulatory infertile women.Clark AM. Hum Reprod 1995 Treatment consisted of a 6 months lifestyle intervention program, including physical activity and hypocaloric diet. * P < 0.05

32. Exercise therapy in polycystic ovarysyndrome: a systematic review BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 8-12% of women. Lifestyle modification, including increased physical activity, is the first-line approach in managing PCOS. A systematic review was performed to identify and describe the effect of exercise as an independent intervention on clinical outcomes in PCOS. METHODS: Five databases were searched with no time limit. A pre-specified definition of PCOS was not used. Studies were included if exercise therapy (aerobic and/or resistance) could be evaluated as an independent treatment against a comparison group. Outcomes measured included cardiovascular risk factors [insulin resistance (IR), lipid profiles, blood pressure and weight] and reproductive measures (ovulation, menstrual regularity and fertility outcomes). Quality analysis was performed based on the Cochrane Handbook of Systematic Reviews and the Quality of Reporting of Meta-Analyses checklist. RESULTS: Eight manuscripts were identified (five randomized controlled trials and three cohort studies). All studies involved moderate intensity physical activity and most were of either 12 or 24 weeks duration with frequency and duration of exercise sessions ranging between studies. The most consistent improvements included improved ovulation, reduced IR (9-30%) and weight loss (4.5-10%). Improvements were not dependant on the type of exercise, frequency or length of exercise sessions. CONCLUSIONS: Exercise-specific interventions in PCOS are limited. Studies vary considerably in design, intensity and outcome measures; therefore conclusive results remain elusive. Larger, optimally designed studies are needed to both gain insights into the mechanisms of exercise action and to evaluate the public health impact of exercise of PCOS. Harrison et al. Hum Reprod Update 2011

33. The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study. Ladson G. et al. Fertil Steril. 2011

34. Bariatric surgery Escobar-Morreale HF et al. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab. 2005 Weight loss (36 pts) 41 +/- 9 kg after 12 +/- 5 months was paralleled by decreases in the hirsutism score (from 9.5 +/- 6.8 to 4.9 +/- 4.2; P = 0.001), total (69 +/- 32 to 42 +/- 19 ng/dl; P < 0.02) and free testosterone (from 1.6 +/- 0.7 to 0.6 +/- 0.3 ng/dl; P < 0.005), androstendione (from 4.1 +/- 1.5 to 3.0 +/- 0.9 ng/ml; P < 0.02), and dehydroepiandrosterone sulphate (from 2000 +/- 1125 to 1353 +/- 759 ng/ml; P < 0.005); amelioration of insulin resistance estimated by homeostasis model assessment (from 6.0 +/- 3.0 to 1.6 +/- 1.0; P < 0.001); and restoration of regular menstrual cycles and/or ovulation in all patients.

35. Great balls of fire? Jerry Lee Lewis 1957

36. A possible effect of obesity on male fertility Hammoud A. Fertil Steril 2008

37. MacDonald AA, Herbison GP, Showell M, Farquhar CM. The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Hum Reprod Update. 2010; 16):293-311. BACKGROUND: It has been suggested that body mass index (BMI), especially obesity, is associated with subfertility in men. Semen parameters are central to male fertility and reproductive hormones also play a role in spermatogenesis. This review aimed to investigate the association of BMI with semen parameters and reproductive hormones in men of reproductive age. METHODS: MEDLINE, EMBASE, Biological Abstracts, PsycINFO and CINAHL databases andreferences from relevant articles were searched in January and February 2009. Outcomes included for semen parameters were sperm concentration, total sperm count, semen volume, motility and morphology. Reproductive hormones included were testosterone, free testosterone, estradiol, FSH, LH, inhibin B and sex hormone binding globulin (SHBG). A meta-analysis was conducted to investigate sperm concentration and total sperm count. RESULTS: In total, 31 studies were included. Five studies were suitable for pooling and the meta-analysis found no evidence for a relationship between BMI and sperm concentration or total sperm count. Overall review of all studies similarly revealed little evidence for a relationship with semen parameters and increased BMI. There was strong evidence of a negative relationship for testosterone, SHBG and free testosterone with increased BMI. CONCLUSIONS: This systematic review with meta-analysis has not found evidence of an association between increased BMI and semen parameters. The main limitation of this review is that data from most studies could not be aggregated for meta-analysis.Population-based studies with larger sample sizes and longitudinal studies are required.

38. Conclusions Weight extremes are associated with anovulatory infertility Obesity adversely affects fertility in ovulatory women The exact mechanisms for why obesity induces infertility is not completely known Weight reduction restores fertility Obesity increases the risk of early miscarriage by mechanisms so far unknown Whether male fertility is affected by overweight/obesity is so far unknown