Insulin sensitizing agents use in pregnancy and as therapy in PCOS

1. Insulin sensitizing agents use in pregnancy and as therapy in PCOS J. SERNA MD. PhD. IVI Madrid

2. TREAT WHAT? Imparied Treatment Options Weight/Metabolic Diet/lifestyle Metformin Dysfunctional bleeding Cyclic progesterone OCP Infertility Metformin Clomiphene Letrozole Gonadotropins Ovarian cautery Skin OCP + antiandrogen (spironolactone, flutamide, finasteride) GnRH agonists

3. Type II anovulatory patients: treatment options • Diet and exercise • Clomiphene citrate, Tamoxiphene • Aromatase Inhibitors • Insulin-Sensitizing Agents • Gonadotropins • FIV-ICSI +/- IVM • Ovarian drilling

4. TREAT WHAT? Imparied Treatment Options Weight/Metabolic ISA Dysfunctional bleeding ISA Infertility ISA Skin ISA

6. CLOMIPHENE INDUCTION OF OVULATION IN PCOS • Bad prognostic factors: • BMI >31 • Increased androgens • Amenorrhea • Older patients • Alternatives/associations: • Metformin if IR • hCG • Glucocorticoids • Gonadotropins • Ovarian drilling • Non wanted effects: • Cervical mucus, endometrium ?? • Vascular side effects (11%) visual side effects (2%) • MP 7%, OHSS, SAB ??

7. BMI

8. Insulin-Sensitizing Agents • α-Glucosidasa Inhibitors • Sulfonilureas • Methiglinides • Biguanides • Thiazolidindiones

11. PREGANACY WANTED

12. Therapeutical Scheme for PCOS Ovulation Aromatase inhibitors?? Drilling???

14. Ovulation Induction vs. Ovarian Stimulation Ovarian Stimulation Ovulation Induction Women with anovulation Women ovulating Restore oocyte production Increase # oocyte production Monofollicular cycle Polyfollicular cycle

15. Main purpose of ovulation induction

16. Ovulation and pregnancy OHSS Multiple Pregnancy Anovulation Normal Ovary Polycystic Ovary

17. Chance of ovulation and of a live birth after CC Imani B. Fertil Steril 2001.

18. Baillargeon et al. 2004

19. Baillargeon et al. 2004

20. Baillargeon et al. 2004

21. Induces ovulation 6 to 8 folds • Decreases Serum Testosterone • Metformin, but not Rosiglitazone, improves HOMA IS • Rosiglitazone improves ovulation despite no significant improvements in insulin parameters

22. MetforminvsNo Treatment vs. CC: etaanalysis

23. 209 CC 208 Metformin 6 months of treatment 209 CC+Metformin 626 patients 6% 0% 3% CC: 22% Metformin: 7% CC+Metformin:26% Multiple pregnancy Live birth rate: First-trimester pregnancy loss did NOT differ among the groups

24. CONCLUSIONS: CC is > to metformin in achieving live birth in PCOS, although multiple birth is a complication. No advantage of the combination therapy over the CC Independently of treatment, BMI < 30 had a higher rate of live births Ovulation rate was higher in the combination group

25. METFORMIN & IVF

26. METFORMINA + FSH vs FSH Fedorsäck (2003) • 17 PCOS + IR women  2 cycles with and without metformin • BMI: 32,0 kg/m2 • Metf.  do not decreases FSH units needed • Metf.  more oocytes were retrieved

27. METFORMINA + FSH vs FSH SOLO Kjotrod (2004 ) • RCT double-blinded, placebo-controlled • 73 patients random. (BMI><28kg /m2 ): • Placebo/metf. 1000mg /day during 16 weeks

28. METFORMINA + FSH vs FSH SOLO Kjotrod (2004 ) • Duration of stimulation • Estradiol hCG day • Oocyte number + fertilization rate • Embryo quality • Pregnancy rate SIGNIFICANT DIFFERENCES ONLY IN PCOS BMI< 28 Clinical Pregnancy Rate

29. METFORMIN & PREGNANCY

30. Rationale • Is it recommended to continue with metformin during pregnancy? • How long? • Which doses? • Which is the safety profile?

31. SAB, GD • PCOS patients do have an increased abortion rate • Jakubowicz ------------- 42% • Glueck ------------- 39-73% • Wang ------------- 25% • PCOS patients do have an increased incidence of gestational diabetes • 46% risk

32. Risk factors: • Hyperinsulinemia, Insulin Resistance • Hyperandrogenemia • Obesity • High PAI-Fas levels inducing hypofibrinolysis • Hyperhomocysteinemia

33. 1st trimester • Jakubowicz et al, JCEM 2002 • Retrospective study in patients with PCOS:

34. 1st trimester • Jakubowicz et al, JCEM 2002 • Retrospective study in patients with PCOS:

35. 1st trimester • Glueck et al: • Decreased SAB rate

36. Gestational Diabetes • Pregnancy induces a physiologic insulin-resistance increasing insulin needs • PCOS women do have a 46% risk for GD

37. Gestational Diabetes • Glueck et al: • Decreased GD incidence. Fertil Steril, 2002; Hum Reprod, 2002 Hum Reprod, 2004 • Metformin + diet: • Previous and During Pregnancy Weight Reduction • Weight • [] Insulin, Insulin resistance, Testosterone • Decreased Risk of GD

38. Safety Profile • FDA group B Either animal-reproduction studies have not shown a fetal risk but there are no controlled studies in women, or animal studies have shown an adverse effect not confirmed by controlled studies in women • Breast-feeding Hale et al, Diabetologia,2002 • Mean doses 1500 mg/day • Mean concentration in babies: 0,28% • < 10%dosage allowed

39. Small studies non-controlled and short duration Different Bias Most of the obese patients non controlled for hyperinsulinemia Metformin & Pregnancy

40. CONCLUSIONS

41. CONCLUSIONS

42. Thank you