ART FOR PCOS-DIFFICULTIES AND SOLUTIONS Dr. Bulent Urman American Hospital, ISTANBUL Assisted Reproduction Unit Koç University, Faculty of Medicine Department of OB/GYN

Consensus on infertility treatment related to PCOS FIRST LINE CLOMIPHENE CITRATE SECOND LINE LOD/GONADOTROPINS THIRD LINE IVF The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March 2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008 RESISTANCE RESISTANCE FAILURE

Does Ovulation = Live Birth ? Legro et al Hum Reprod 2004

Surgical induction of ovulation Wedge resection by LT LOD Publications1811 Patients Ovulation Pregnancy Adhesions Moderate to severe Minimal to mild From 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 STIMULATION OVER STIMULATION UNDER STIMULATION Normal responder 300

OPTIMAL STIMULATION OVER STIMULATION UNDER STIMULATION Hyper responder Hyper 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 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); 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 Hum. Rep. 21(6);1387 – 1399 Moll et al Hum. Reprod. Update 13(6);

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 outcome From Bellver et al. Fertil Steril 2010

Metformin co-treatment

Metformin prior to and during IVF MetforminPlaceboP value Number of patients5249 CPR>12 weeks38.5%16.3%P=0.02 Live birth rate32.7%12.2%P=0.027 Severe OHSS3.8%20.4%P=0.023 Side effects45.1%8.2%P=0.001 All patients treated with luteal long protocol Metformin started on the first day of down regulation Dose 2 x 850 mg/day From Tang et al. Hum Reprod 2006

Metformin 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 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/yearStudy TypeNo of cyclesGnRHa usedPregnancyOHSS Bankowski 2004 Retro comparative 971 mg LACPR 11.3None Erden 2005Retro Cohort mg TRCPR 41.0NR Shapiro 2005 Retro Cohort mg LACPR 31.0None severe Bar Hava 2005 Observat670.2 mg TRCPR 30.01/67 Koresi 2006Retro comparative TRCPR 28.0NR

GnRHa triggering of oocyte maturation-RCT From Engman et al. Fertil Steril 2008

GnRHa triggering of oocyte maturation-RCT From Engman et al. Fertil Steril 2008

ReferenceOvulation trigger nLPSClinical Pregnancy% (n) Ongoing pregnancy % (n) Delivery rate % (n) P- value Humaidan et al. (2005) GnRHa55P 90 mg (8%) vag + 4 mg oral E2 6 (3/55) hCG67P 90 mg (8%) vag + 4 mg oral E2 36 (24/67) Kolibianakis et al. (2005) GnRHa50P 600 mg vag + 4 mg oral E2 *5.6 (1/18)* (1/34) hCG54P 600 mg vag + 4 mg oral E2 *41.7 (10/24)* 16.7 (5/30) Humaidan et al. (2006) GnRHa IU hCG OPU day + P 90 mg (8%) vag + 4 mg oral E2 46 (6/13)38 (5/13) 0.43 hCG15P 90 mg (8%) vag + 4 mg oral E2 53 (8/15) Pirard et al. (2006) GnRHa6GnRHa nasal 100 µg IN 3xd 33 (2/6)**0.51 hCG6P 600 mg vag17 (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) ReferenceOvulation trigger nLPSClinical Pregnancy % (n) Ongoing pregnancy % (n) Delivery rate % (n) P- value Babayof et al. (2006) GnRHa15P 50 i.m. 100 mg ± 4 mg oral E2 20 (3/15)6.6 (1/15) 0.46 hCG13P 50 i.m. 100 mg ± 4 mg oral E2 31 (4/13)15 (2/13) Engmann et al. (2008) GnRHa33P 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 hCG3250 mg P i.m.47 (15/32)44 (14/32)* Humaidan et al. (2009) GnRHa IU hCG OPU day + P 90 mg (8%) vag + 4 mg oral E2 33 (50/152)26 (40/152)24 (36/152) 0.16 hCG15 0 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 maturation-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 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