Transcript MODERN APPROACH TO PCOS

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
Type II anovulatory patients: treatment options
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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
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
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α-Glucosidasa Inhibitors
Sulfonilureas
Methiglinides
Biguanides
Thiazolidindiones
PREGANACY WANTED
Therapeutical Scheme for PCOS Ovulation
Aromatase inhibitors??
Drilling???
Ovulation Induction vs. Ovarian Stimulation
Ovulation Induction
Women with
anovulation
Restore oocyte
production
Monofollicular cycle
Ovarian Stimulation
Women
ovulating
Increase # oocyte
production
Polyfollicular cycle
Main purpose of ovulation induction
Ovulation and
pregnancy
Normal Ovary
Anovulation
OHSS
Multiple Pregnancy
Polycystic Ovary
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
626 patients
Live birth rate:
209 CC
208 Metformin
209 CC+Metformin
CC: 22%
Metformin: 7%
CC+Metformin:26%
6 months of treatment
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 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
 Glueck
 Wang
------------- 42%
------------- 39-73%
------------- 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
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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:
 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 noncontrolled and
short duration
 Different Bias
 Most of the obese
patients non
controlled for
hyperinsulinemia
CONCLUSIONS
CONCLUSIONS
Thank you