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

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

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

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

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 ??

BMI

Insulin-Sensitizing Agents α-Glucosidasa Inhibitors Sulfonilureas Methiglinides Biguanides Thiazolidindiones

PREGANACY WANTED

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

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

Main purpose of ovulation induction

Ovulation and pregnancy OHSS Multiple Pregnancy Anovulation Normal Ovary Polycystic Ovary

x x OVULATION INDUCTION Two mechanisms - DIRECT ACTION INDIRECT ACTION Clomiphene GnRH - Estrogens Gonadotropins x Aromatase inhibitors  Decrease androstenedione conversion to estrogens

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

Baillargeon et al. 2004

Baillargeon et al. 2004

Baillargeon et al. 2004

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

Metformin vs No Treatment vs. CC: etaanalysis

First-trimester pregnancy loss did NOT differ among the groups 209 CC 208 Metformin 6 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

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

METFORMIN & IVF

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

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

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

METFORMIN & PREGNANCY

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

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

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

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

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

1st trimester Glueck et al: Decreased SAB rate

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

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

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

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

CONCLUSIONS

CONCLUSIONS

Thank you