ART FOR PCOS-DIFFICULTIES AND SOLUTIONS

Dr. Bulent UrmanAmerican Hospital, ISTANBUL

Assisted Reproduction UnitKoç University, Faculty of Medicine

Department of OB/GYN

Consensus on infertility treatment related to PCOS

FIRST LINEFIRST LINECLOMIPHENE CITRATE

SECOND LINESECOND LINELOD/GONADOTROPINS

THIRD LINETHIRD LINEIVF

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March 2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008

RREESSIISSTTAANNCCEE

RREESSIISSTTAANNCCEE

FFAAIILLUURREE

Fetal Viability

Ovulation

Fertilization

Implantation

Healthy Liveborn

?Poor Oocyte Quality

?EndometrialAbnormality

?EffectsHyperinsulinemia

? Effects gestationaldiabetes andhypertension

Does Ovulation = Live Birth ?

Legro et al Hum Reprod 2004

Surgical induction of ovulationSurgical induction of ovulation

Wedge Wedge resection by LTresection by LT

LODLOD

PublicationsPublications 1818 1111

PatientsPatients 17661766 729729

OvulationOvulation 74.674.6 84.284.2

PregnancyPregnancy 58.858.8 55.755.7

AdhesionsAdhesions Moderate to Moderate to severesevere

Minimal to mildMinimal to mild

From Urman and Yakin JRM 2006From Urman and Yakin JRM 2006

Challenges of treating infertility with IVF in the PCOS/PCO patient

• Propensity for an exaggerated ovarian response

• Difficulties in titrating gonadotropin dose• Increased risk of cycle cancellation• Increased incidence of early and late OHSS• Increased risk of spontaneous pregnancy loss

Optimal ovarian stimulation for IVF

• Avoid understimulation• Avoid overstimulation• Minimize cycle cancellation• Minimize if not avoid altogether OHSS

FSH

OPTIMAL STIMULATIONOPTIMAL STIMULATION

OVER STIMULATIONOVER STIMULATION

UNDER STIMULATIONUNDER STIMULATION

150225

Normal responderNormal responder

300

OPTIMAL STIMULATIONOPTIMAL STIMULATIONOVER STIMULATIONOVER STIMULATION

UNDER STIMULATIONUNDER STIMULATION

150187.5

Hyper responderHyper responder

112.5

PCOS AND OHSS

Artini et al. Human fertility 2009;12:40

VEGF induced permeability

Nature Rev Cancer;2005:437:497

hCG

VEGF induced permeabilityVEGF induced permeability

Nature Rev Cancer;2005:437:497

Insulin resistance and OHSS

• Insulin is a stimulator of VEGF secretion in vascular endothelial cells.

Doronzo et al. Eur. J. Clin. Invest. 34(10); 664 - 673

• Effect of metformin on OHSS seems to be mediated by declined insulin levels

Metformin and OHSS

• Two meta-analyses found that metformin co-administration in PCOS women undergoing IVF decreased the incidence of OHSS

• The beneficial effect was observed in all RCTs regardless of duration and dosage of metformin

• Number of oocytes collected and peak E2 levels were unaffected by metformin

Costello et al. 2006 Hum. Rep. 21(6);1387 – 1399

Moll et al. 2007 Hum. Reprod. Update 13(6); 527 - 537

VEGF induced permeability

Nature Rev Cancer;2005:437:497

Cabergoline inhibits phosphorylation of VEGR2

Gomez et al Endocrinology 2006;147:5400

hCG

PreIVF considerations

• Weight loss in overweight women• Metformin• LOD

Impact of weight on IVF outcomeImpact of weight on IVF outcome

From Bellver et al. Fertil Steril 2010From Bellver et al. Fertil Steril 2010

Metformin co-treatment

Metformin prior to and during IVF

Metformin Placebo P value

Number of patients 52 49

CPR>12 weeks 38.5% 16.3% P=0.02

Live birth rate 32.7% 12.2% P=0.027

Severe OHSS 3.8% 20.4% P=0.023

Side effects 45.1% 8.2% P=0.001

All patients treated with luteal long protocolMetformin started on the first day of down regulationDose 2 x 850 mg/day

From Tang et al. Hum Reprod 2006

Metformin co-treatmentMetformin co-treatment

From Moll et al. Hum Reprod Update 2007

Laparoscopic ovarian drilling as an adjunct to IVF

• May decrease the frequency and severity of OHSS in women with a previous episode of OHSS

• May facilitate ovarian stimulation in the brittle PCOS patient (Ferraretti, Fertil Steril 2001)

Ovarian stimulation for IVF in the PCOS patient

• Type of gonadotropin?• How to suppress LH surge and premature

luteinization (agonist vs antagonist)?• How to trigger final oocyte maturation?• Coasting

Urinary vs recFSH in women with PCOS undergoing IVF-RCT

Agonist vs antagonistAgonist vs antagonist

From Kurzawa et al. J Assist Reprod Genet 2008

Agonist vs antagonist-RCT

From Lainas et al. Hum Reprod 2010

GnRH triggering of final oocyte maturation

GnRHa triggering of final oocyte maturation in patients at risk for OHSS

Author/year Study Type No of cycles GnRHa used Pregnancy OHSS

Bankowski 2004

Retro comparative

97 1 mg LA CPR 11.3 None

Erden 2005 Retro Cohort

97 0.2 mg TR CPR 41.0 NR

Shapiro 2005

Retro Cohort

30 4-8 mg LA CPR 31.0 None severe

Bar Hava 2005

Observat 67 0.2 mg TR CPR 30.0 1/67

Koresi 2006 Retro comparative

25 0.1-0.2 TR CPR 28.0 NR

GnRHa triggering of oocyte GnRHa triggering of oocyte maturation-RCTmaturation-RCT

From Engman et al. Fertil Steril 2008From Engman et al. Fertil Steril 2008

GnRHa triggering of oocyte GnRHa triggering of oocyte maturation-RCTmaturation-RCT

From Engman et al. Fertil Steril 2008From Engman et al. Fertil Steril 2008

Reference Ovulation trigger

n LPS Clinical Pregnancy% (n)

Ongoing pregnancy % (n)

Delivery rate % (n)

P-value

Humaidan et al. (2005)

GnRHa 55 P 90 mg (8%) vag + 4 mg oral E2

6 (3/55) 6 (3/55) 6 (3/55) 0.002

hCG 67 P 90 mg (8%) vag + 4 mg oral E2

36 (24/67) 36 (24/67) 36 (24/67)

Kolibianakis et al. (2005)

GnRHa 50 P 600 mg vag + 4 mg oral E2

* 5.6 (1/18) * 0.005

2.9 (1/34)

hCG 54 P 600 mg vag + 4 mg oral E2

* 41.7 (10/24) *

16.7 (5/30)

Humaidan et al. (2006)

GnRHa 13 1500 IU hCG OPU day + P 90 mg (8%) vag + 4 mg oral E2

46 (6/13) 38 (5/13) 38 (5/13)

0.43

hCG 15 P 90 mg (8%) vag + 4 mg oral E2

53 (8/15) 53 (8/15) 53 (8/15)

Pirard et al. (2006)

GnRHa 6 GnRHa nasal 100 µg IN 3xd

33 (2/6) * * 0.51

hCG 6 P 600 mg vag 17 (1/6) * *

Main characteristics, luteal phase support and reproductive outcome of published RCT on GnRHa triggering of final oocyte maturation

Humaidan et al. Hum Reprod 2009

Main characteristics, luteal phase support and reproductive outcome of published RCT on GnRHa triggering of final oocyte maturation (intention to treat)

Reference Ovulation trigger

n LPS Clinical Pregnancy % (n)

Ongoing pregnancy % (n)

Delivery rate % (n)

P-value

Babayof et al. (2006)

GnRHa 15 P 50 i.m.   100 mg ± 4 mg oral E2

20 (3/15) 6.6 (1/15) 6.6 (1/15)

0.46

hCG 13 P 50 i.m.   100 mg ± 4 mg oral E2

31 (4/13) 15 (2/13) 15 (2/13)

Engmann et al. (2008)

GnRHa 33 P 50 i.m.   75 mg + E2 patches 3–4 x 0.1 mg/2d ± 4 mg oral E2

52 (17/33) 48 (16/33) * 0.90

hCG 32 50 mg P i.m. 47 (15/32) 44 (14/32) *

Humaidan et al. (2009)

GnRHa 152

1500 IU hCG OPU day + P 90 mg (8%) vag + 4 mg oral E2

33 (50/152) 26 (40/152) 24 (36/152)

0.16

hCG 150

P 90 mg (8%) vag + 4 mg oral E2

37 (55/150) 33 (49/150) 31 (47/150)

Humaidan et al. Hum Reprod 2009

GnRHa triggering of oocyte GnRHa triggering of oocyte maturation-hints and tipsmaturation-hints and tips

• Lower implantation rates reported in some studies may be attributed to the luteolytic effect of the GnRHa

• Titration of the luteal phase support is important

Optimal cycle management in the PCOS patient

• Careful titration of the gonadotropin dose• Measures to prevent OHSS

– Coasting– GnRHa for triggering final oocyte maturation– Single Blast transfer vs Cryopreservation of all

embryos– Cabergoline

Outcome of IVF in PCOSOutcome of IVF in PCOS

Outcome of IVF in women with PCOS vs controls

From Urman et al. RBM Online 2004

PCOS TUBAL/OTHER

Outcome of IVF in women with PCOS vs controls

From Urman et al. RBM Online 2004

Cumulative PR in PCOS vs controls

From Pirinen et al. Gynecol Endocrinol 2010

From Heijnen Hum Reprod Update 2006

IVM

From Suikkari, Curr Opin Obstet Gynecol 2008

Clinical outcome of IVM in PCOS or PCO

IVM vs IVF in PCOS

• Randomized trials do not exist• Comparative studies, noncomparative case

series and randomized trials comparing different protocols of IVM show:– Favorable maturation, fertilization, pregnancy

and live birth rates with IVM compared to IVF– The rate of congenital anomalies appear to be

similar– Urgent randomized trials are needed

Conclusions

• PCOS patient is the most difficult to treat with IVF

• Cycle cancellation rates and risk of OHSS are higher

• Fine tailoring of ovarian stimulation is necessary to avoid complications

• Treating physicians should be aware of the difficulties and remedies/solutions