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Insulin sensitizing agents use in pregnancy and as therapy in PCOS
J. SERNA MD. PhD. IVI Madrid
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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
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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
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TREAT WHAT? Imparied Treatment Options Weight/Metabolic
ISA Dysfunctional bleeding ISA Infertility ISA Skin ISA
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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 ??
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BMI
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Insulin-Sensitizing Agents
α-Glucosidasa Inhibitors Sulfonilureas Methiglinides Biguanides Thiazolidindiones
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PREGANACY WANTED
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Therapeutical Scheme for PCOS Ovulation
Aromatase inhibitors?? Drilling???
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Ovulation Induction vs. Ovarian Stimulation
Women with anovulation Women ovulating Restore oocyte production Increase # oocyte production Monofollicular cycle Polyfollicular cycle
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Main purpose of ovulation induction
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Ovulation and pregnancy
OHSS Multiple Pregnancy Anovulation Normal Ovary Polycystic Ovary
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x x OVULATION INDUCTION Two mechanisms - DIRECT ACTION INDIRECT ACTION
Clomiphene GnRH - Estrogens Gonadotropins x Aromatase inhibitors Decrease androstenedione conversion to estrogens
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Chance of ovulation and of a live birth after CC
Imani B. Fertil Steril 2001.
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Baillargeon et al. 2004
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Baillargeon et al. 2004
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Baillargeon et al. 2004
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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
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Metformin vs No Treatment vs. CC: etaanalysis
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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
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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
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METFORMIN & IVF
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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
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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
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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
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METFORMIN & PREGNANCY
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Rationale Is it recommended to continue with metformin during pregnancy? How long? Which doses? Which is the safety profile?
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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
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Risk factors: Hyperinsulinemia, Insulin Resistance Hyperandrogenemia
Obesity High PAI-Fas levels inducing hypofibrinolysis Hyperhomocysteinemia
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1st trimester Jakubowicz et al, JCEM 2002
Retrospective study in patients with PCOS:
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1st trimester Jakubowicz et al, JCEM 2002
Retrospective study in patients with PCOS:
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1st trimester Glueck et al: Decreased SAB rate
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Gestational Diabetes Pregnancy induces a physiologic insulin-resistance increasing insulin needs PCOS women do have a 46% risk for GD
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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
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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
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Metformin & Pregnancy Small studies non-controlled and short duration
Different Bias Most of the obese patients non controlled for hyperinsulinemia
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CONCLUSIONS
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CONCLUSIONS
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Thank you
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