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. Clomiphene citrate, Tamoxiphene Aromatase Inhibitors
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. Bad prognostic factors:
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
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. x x OVULATION INDUCTION Two mechanisms - DIRECT ACTION INDIRECT ACTION
Clomiphene
GnRH -
Estrogens
Gonadotropins x
Aromatase inhibitors
 Decrease androstenedione conversion to estrogens

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

19. Baillargeon et al. 2004

20. Baillargeon et al. 2004

21. Baillargeon et al. 2004

22. 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

23. Metformin vs No Treatment vs. CC: etaanalysis

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

25. No advantage of the combination therapy over the CC
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

26. METFORMIN & IVF

27. 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

28. 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

29. 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

30. METFORMIN & PREGNANCY

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

32. SAB, GD PCOS patients do have an increased abortion rate
Jakubowicz %
Glueck %
Wang %
PCOS patients do have an increased incidence of gestational diabetes
46% risk

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

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

35. 1st trimester Jakubowicz et al, JCEM 2002
Retrospective study in patients with PCOS:

36. 1st trimester
Glueck et al:
Decreased SAB rate

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

38. Gestational Diabetes Glueck et al: Metformin + diet:
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

39. 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

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

41. CONCLUSIONS

42. CONCLUSIONS

43. Thank you