Insulin sensitizing agents use in Insulin sensitizing agents use in pregnancy and as therapy in PCOSpregnancy and as therapy in PCOS

J. SERNA MD. PhD.IVI Madrid

TREAT WHAT?

MetforminClomipheneLetrozoleGonadotropinsOvarian cautery

Infertility

OCP + antiandrogen (spironolactone, flutamide, finasteride)GnRH agonists

Skin

Cyclic progesteroneOCPDysfunctional bleeding

Diet/lifestyleMetforminWeight/Metabolic

Treatment OptionsImparied

Type II anovulatory patients: treatment optionsType II anovulatory patients: treatment options

Diet and exercise Clomiphene citrate, Tamoxiphene Aromatase Inhibitors Insulin-Sensitizing Agents Gonadotropins FIV-ICSI +/- IVM Ovarian drilling

TREAT WHAT?

ISAInfertility

ISASkin

ISADysfunctional bleeding

ISAWeight/Metabolic

Treatment OptionsImparied

CLOMIPHENE INDUCTION OF OVULATION IN PCOSCLOMIPHENE INDUCTION OF OVULATION IN PCOS

Bad prognostic factors:BMI >31Increased androgensAmenorrheaOlder 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

α-Glucosidasa Inhibitors Sulfonilureas Methiglinides Biguanides Thiazolidindiones

α-Glucosidasa Inhibitors Sulfonilureas Methiglinides Biguanides Thiazolidindiones

Insulin-Sensitizing Agents

PREGANACY WANTEDPREGANACY WANTED

Drilling???Drilling???

Aromatase inhibitors??Aromatase inhibitors??

Therapeutical Scheme for PCOS OvulationTherapeutical Scheme for PCOS Ovulation

Women with anovulation

Women ovulating

Ovulation InductionOvarian Stimulation

Restore oocyte production

Increase # oocyte production

Monofollicular cycle Polyfollicular cycle

Ovulation Induction vs. Ovarian StimulationOvulation Induction vs. Ovarian Stimulation

Main purpose of ovulation inductionMain purpose of ovulation induction

Normal OvaryNormal Ovary

Polycystic OvaryPolycystic Ovary

Anovulation

OHSSMultiple

Pregnancy

Ovulation and pregnancy

Imani B. Fertil Steril 2001.

Chance of ovulation and of a live birth after CCChance of ovulation and of a live birth after CC

Baillargeon et al. 2004

Baillargeon et al. 2004

Baillargeon et al. 2004

Induces ovulation 6 to 8 foldsInduces ovulation 6 to 8 folds Decreases Serum TestosteroneDecreases Serum Testosterone Metformin, but not Rosiglitazone, Metformin, but not Rosiglitazone,

improves HOMA ISimproves HOMA IS Rosiglitazone improves ovulation Rosiglitazone improves ovulation

despite no significant improvements despite no significant improvements in insulin parametersin insulin parameters

Metformin vs No Treatment vs. CC: etaanalysisMetformin vs No Treatment vs. CC: etaanalysis

626 patients209 CC208 Metformin 6 months of treatment209 CC+Metformin

Live birth rate:CC: 22%Metformin: 7%

CC+Metformin:26% Multiple pregnancy

6%0%3%

First-trimester pregnancy loss did NOT differ among the groups

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 FSHFedorsäck (2003)

METFORMINA + FSH vs FSHFedorsäck (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 SOLOKjotrod (2004 )

METFORMINA + FSH vs FSH SOLOKjotrod (2004 )

RCT double-blinded, placebo-controlled

73 patients random. (BMI><28kg /m2 ):

Placebo/metf. 1000mg /day during 16 weeks

Duration of stimulation

Estradiol hCG day

Oocyte number + fertilization rate

Embryo quality

Pregnancy rate

METFORMINA + FSH vs FSH SOLOKjotrod (2004 )

METFORMINA + FSH vs FSH SOLOKjotrod (2004 )

SIGNIFICANT DIFFERENCES ONLY IN PCOS BMI< 28 Clinical Pregnancy Rate

METFORMIN & PREGNANCY

RationaleRationale

Is it recommended to continue with Is it recommended to continue with metformin during pregnancy?metformin during pregnancy?

How long?How long? Which doses?Which doses? Which is the safety profile?Which is the safety profile?

SAB, GD PCOS patients do have an increased PCOS patients do have an increased

abortion rateabortion rate Jakubowicz ------------- 42%Jakubowicz ------------- 42% Glueck ------------- 39-73%Glueck ------------- 39-73% Wang ------------- 25%Wang ------------- 25%

PCOS patients do have an increased PCOS patients do have an increased incidence of gestational diabetes incidence of gestational diabetes 46% risk46% risk

Risk factors:Risk factors:

Hyperinsulinemia, Insulin ResistanceHyperinsulinemia, Insulin Resistance HyperandrogenemiaHyperandrogenemia ObesityObesity High PAI-Fas levels inducing High PAI-Fas levels inducing

hypofibrinolysishypofibrinolysis HyperhomocysteinemiaHyperhomocysteinemia

1st trimester

Jakubowicz et alJakubowicz et al, , JCEM 2002JCEM 2002 Retrospective study in patients with

PCOS:

1st trimester

Jakubowicz et alJakubowicz et al, , JCEM 2002JCEM 2002 Retrospective study in patients with

PCOS:

1st trimester

Glueck et al:Glueck et al: Decreased Decreased SAB SAB raterate

Gestational Diabetes

Pregnancy induces a physiologic Pregnancy induces a physiologic insulin-resistance increasing insulin insulin-resistance increasing insulin needs needs

PCOS women do have a 46% risk for PCOS women do have a 46% risk for GDGD

Gestational Diabetes Glueck et al:Glueck et al:

Decreased GD incidence.Decreased GD incidence.Fertil Steril, 2002; Hum Reprod, 2002Fertil Steril, 2002; Hum Reprod, 2002Hum Reprod, 2004Hum Reprod, 2004

Metformin + diet: Metformin + diet: Previous and During Pregnancy Weight Previous and During Pregnancy Weight

ReductionReduction WeightWeight [] Insulin, Insulin resistance, Testosterone[] Insulin, Insulin resistance, Testosterone

Decreased Risk of GD Decreased Risk of GD

Safety Profile FDA group BFDA group B

Either animal-reproduction studies have not Either animal-reproduction studies have not shown a fetal risk but there are no shown a fetal risk but there are no controlled studies in women, ocontrolled studies in women, orr animal animal studies have shown an adverse effect not studies have shown an adverse effect not confirmed by controlled studies in womenconfirmed by controlled studies in women

Breast-feeding Breast-feeding Hale et al, Diabetologia,2002Hale et al, Diabetologia,2002 Mean doses 1500 mg/day Mean doses 1500 mg/day Mean concentration in babies: 0,28%Mean concentration in babies: 0,28% < 10%< 10% dosage dosage allowed allowed

Metformin & Pregnancy Small studies non-Small studies non-

controlled and controlled and short duration short duration

Different BiasDifferent Bias Most of the obese Most of the obese

patients non patients non controlled for controlled for hyperinsulinemiahyperinsulinemia

CONCLUSIONS

CONCLUSIONS

Thank you