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The approach to the PCOS patient undergoing IVF Roy Homburg Barzili Medical Centre, Ashkelon, The approach to the PCOS patient undergoing IVF Roy Homburg Barzili Medical Centre, Ashkelon, Israel and Homerton University Hospital, London Antalya, October 2011

Problems – IVF for PCOS • Excessive ovarian response • • • Low fertilization Problems – IVF for PCOS • Excessive ovarian response • • • Low fertilization rates High number of immature oocytes Reduced cleavage rates Low implantation rates High miscarriage rates

Overcoming the problems for PCOS in IVF Diagnosis and mild stimulation Agonist vs antagonist Overcoming the problems for PCOS in IVF Diagnosis and mild stimulation Agonist vs antagonist Oral contraceptive pre-treatment Gn. RH agonist to trigger ovulation Metformin Freeze embryos IVM

Comparison of the long protocol and the antagonist protocols ultiple dose protocol no cyst Comparison of the long protocol and the antagonist protocols ultiple dose protocol no cyst formation more physiologic no hormonal withdrawal antagonist administration Patient-friendly gonadotropin administration less gonadotropins early Menses pregnancy? flare up pituitary gonadotropin administration effect suppression long protocol agonist administration (mid-luteal) longer treatment pre-treatment cycle

4. 1% 2. 6% 4. 1% 2. 6%

Hospital admission due to OHSS RR: 0. 47 ~50% less risk for hospital admission Hospital admission due to OHSS RR: 0. 47 ~50% less risk for hospital admission due to OHSS with Gn. RH antagonists Kolibianakis et al. Hum Reprod Update. 2006

Gn. RH antagonists are safer than agonists: an update of a Cochrane review. Al-Inany Gn. RH antagonists are safer than agonists: an update of a Cochrane review. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, Abou-Setta AM. Hum Reprod Update, May 2011

Finally…. . no difference in live birth rate 2011 May 11, 2011 With new Finally…. . no difference in live birth rate 2011 May 11, 2011 With new information available, authors of a Cochrane Systematic Review have revised their conclusions about the relative effectiveness of two different treatments used to help women become pregnant. They now conclude that giving women Gn. RH-antagonists leads to similar live-birth rates compared with Gn. RH agonists. Previously they had concluded that women who used antagonists tended to have lower birth-rates than those using agonists. [. . . . ] In 2006, when the researchers reached their earlier conclusion, they were only able to draw data from 27 trials. Since then more research has been published, allowing them to consider the findings of 45 randomised controlled studies that involved a total of 7, 511 women. “This increased amount of data lets us get a much better idea of how well the two approaches compare, ” says Dr Hesham Al-Inany, who was lead author of the research and works at Cairo University, Egypt. Dr Al-Inany led a multi-centre team, with researchers also based in the Netherlands and Canada. “The reduction in ovarian hyperstimulation combined with a comparable live-birth rate mean justifies a move away from the standard Gn. RH agonist to using Gn. RH antagonists, ” says Dr Al-Inany. http: //eu. wiley. com/Wiley. CDA/Press. Release/press. Release. Id-9635

F&S 2008 18. 1% vs 23. 6% F&S 2008 18. 1% vs 23. 6%

- OC pretreated Starting with Gn on day 2/3 after the last OC intake. - OC pretreated Starting with Gn on day 2/3 after the last OC intake. Fixed Gn. RH antagonist regimen (long-starting SD 1)- Huirne et al, 2007

Incidence of OHSS Objective: to determine OHSS incidence in 2, 524 antagonist. Objective based Incidence of OHSS Objective: to determine OHSS incidence in 2, 524 antagonist. Objective based cycles (1801 patients). Results: fifty three patients (2%) were hospitalized because of Results OHSS. Conclusions: clinically significant OHSS is a limitation even in Conclusions antagonist cycles. “There is more than ever an urgent need for alternative final oocyte maturation – triggering F&S January 2006 medication”

0. 25 mg/day antagonist FSH Day 5 , 6 or 7 antagonist start FIXED 0. 25 mg/day antagonist FSH Day 5 , 6 or 7 antagonist start FIXED hcg 0. 25 mg/day antagonist FSH hcg day 8/9 Follicle size 14 mm- start antagonist Flexible regime

0. 25 mg/day antagonist FSH Day 5 , 6 or 7 antagonist start FIXED 0. 25 mg/day antagonist FSH Day 5 , 6 or 7 antagonist start FIXED Gn. RH agonist 0. 25 mg/day antagonist FSH day 8/9 Gn. RH agonist Follicle size 14 mm- start antagonist Flexible regime

Agonist: 1932 patients, not a single case of OHSS! h. CG: 84 cases in Agonist: 1932 patients, not a single case of OHSS! h. CG: 84 cases in 1760 patients, 4. 8% Ovulation trigger n OHSS % (n) RCT, high risk Oocyte source own Gn. RHa h. CG Engamnn et al 2008 RCT, high risk own Gn. RHa h. CG Acevedo et al 2006 RCT donors Gn. RHa h. CG Bodri et al 2009 Retrospective donors Gn. RHa h. CG Griesinger et al 2007 Observational, High risk RCT own Gn. RHa 15 13 33 32 30 30 1046 1031 20 0 (0/13) 31(4/13) 0 (0/33) 31 (10/32) 0 (0/30) 17 (5/30) 0 (0/1046) 1. 3 (13/1031) 0 (0/20) own Gn. RHa h. CG Engmann et al 2006 Retrospective, casecontrolled, high risk own Gn. RHa h. CG 152 150 23 23 0 (0/152) 2 (3/150) 0 (0/23) 4 (1/23) Manzanares et al 2009 Retrospective casecontrol, high risk own Gn. RHa h. CG - cancelled 42 0 (0/42) Hernandez et al 2009 Retrospective donors Gn. RHa h. CG Orvieto et al 2006 Retrospective, high own risk Retrospective, high donors risk: agonist arm only Gn. RHa h. CG 254 175 82 69 32 42 0 (0/254) 6 (10/175) 0 (0/82) 7 (5/69) 0 (0/32) 1 (1/42) Sismanoglu et al 2009 RCT donors Gn. RHa h. CG Humaidan et al 2009 Observational, high risk own Gn. RH, luteal rescue with h. CG 1500 IU 44 44 12 0 (0/44) 7 (3/44) 8 (1/12) Galindo et al 2009 RCT donors Gn. RHa h. CG Shahrokh et al 2010 RCT, high risk own Gn. RHa h. CG 106 4 45 0 (0/106) 8 (9/106) 0 (0/45) 15 (33) Reference Trial type Babayof et al 2006 Humaidan et al 2009 Shapiro et al 2007 Gn. RHa h. CG

Agonist versus HCG for oocyte triggering Youssef et al. Cochrane Review 2010 Agonist versus HCG for oocyte triggering Youssef et al. Cochrane Review 2010

0. 25 mg/day antagonist FSH start Gn. RH agonist FIXED Freeze and thaw cycles 0. 25 mg/day antagonist FSH start Gn. RH agonist FIXED Freeze and thaw cycles Luteal phase support

Triggering of final oocyte maturation with Gn. RHa or HCG: Live birth after frozen-thawed Triggering of final oocyte maturation with Gn. RHa or HCG: Live birth after frozen-thawed embryo replacement cycles P = 0. 02 Griesinger et al. , Fertil Steril 2007

Frozen-thawed cycles Manzanares et al, 2009 Frozen-thawed cycles Manzanares et al, 2009

0. 25 mg/day antagonist FSH start FIXED Luteal phase support: 1. Massive doses P 0. 25 mg/day antagonist FSH start FIXED Luteal phase support: 1. Massive doses P +/- E 2 2. 1500 IU h. CG on day OPU (Humaidan 2009) Gn. RH agonist

Gn. RH agonist vs h. CG in high risk IVF patients RCT, n=66 with Gn. RH agonist vs h. CG in high risk IVF patients RCT, n=66 with PCO’s Antag + Gn. RH trigger vs Agonist + h. CG trigger OHSS – 0% vs 31% Ongoing pregnancy rates – 53% vs 48% Adequate E 2 , P supplementation in luteal phase Engmann et al, 2008

0. 25 mg/day antagonist FSH start Gn. RH agonist FIXED Luteal phase support: 1500 0. 25 mg/day antagonist FSH start Gn. RH agonist FIXED Luteal phase support: 1500 IU h. CG on day OPU (Humaidan 2009) No significant difference in outcome compared with h. CG trigger

Gn. RH agonist + 1500 U h. CG on day OPU vs h. CG Gn. RH agonist + 1500 U h. CG on day OPU vs h. CG Variable Gn. RHa h. CG Patients, n 152 OR (95% CI) P Value 150 Clinical (33) 50/152 pregnancy (%) (37) 55/150 (0. 9– 0. 7) 0. 8 29. Ongoing (26) 40/152 pregnancy (%) (33) 49/150 (0. 8– 0. 6) 0. 7 69. Delivery rate (%) (31) 47/150 (0. 8– 0. 6) 0. 7 16. (17) 11/66 (1. 9– 0. 7) 1. 3 36. (24) 36/152 Early pregnancy loss, (21) 13/63 n (% of positive h. CG) Humaidan et al, 2010

Beyond the context of OHSS: Patient-friendly luteal phase • Abdominal pain and discomfort due Beyond the context of OHSS: Patient-friendly luteal phase • Abdominal pain and discomfort due to enlarged ovaries. • How to minimize ovarian volume post oocyte retrieval?

Clinical use of agonist trigger opinion • Primarily in the context of OHSS prevention. Clinical use of agonist trigger opinion • Primarily in the context of OHSS prevention. • Prevention is total. • A major reason to use Gn. RH antagonists in ovarian stimulation of high-risk patients: to keep the option of agonist trigger if needed.

Metformin for IVF • n=73 PCOS for IVF/ICSI - metformin (2 G/d) - placebo Metformin for IVF • n=73 PCOS for IVF/ICSI - metformin (2 G/d) - placebo for 16 weeks • No difference in any stimulation, IVF or clinical criteria. • BUT in group with BMI < 28, pregnancy rates double on metformin. Kjotrod et al, 2004

Metformin in IVF Tang, Bart & Balen, 2005 • Single centre, double-blind RCT • Metformin in IVF Tang, Bart & Balen, 2005 • Single centre, double-blind RCT • 94 patients, PCOS, BMI 27. 8 101 IVF/ICSI cycles, long agonist protocol • Metformin (850 mg bd) or placebo from start of agonist to OPU

Metformin in IVF • No difference: Total dose FSH No. of oocytes Fertilisation rates Metformin in IVF • No difference: Total dose FSH No. of oocytes Fertilisation rates Tang, Barth & Balen, 2005

Metformin for IVF in PCOS P = 0. 02 Tang et al. , Hum Metformin for IVF in PCOS P = 0. 02 Tang et al. , Hum Reprod 2005

Metformin in IVF • Short term co-treatment with metformin for PCOS in IVF/ICSI : Metformin in IVF • Short term co-treatment with metformin for PCOS in IVF/ICSI : • • • Does not improve response to stimulation Improves pregnancy rates Reduces the risk of OHSS Tang, Bart & Balen, 2005

Endometrial dysfunction • Low luteal phase serum glycodelin and IGFBP-1 (Jacubowicz et al, 2001) Endometrial dysfunction • Low luteal phase serum glycodelin and IGFBP-1 (Jacubowicz et al, 2001) • Plasma endothelin-1 levels high in PCOS (Diamantis-Kandarakis et al, 2005) • Inadequate endometrial blood flow et al, 2005) All induced by hyperinsulinemia and improved by metformin. (Orio

IVM from unstimulated PCO N=118 women, PCOS. 152 cycles OPU day 9 -14 ET IVM from unstimulated PCO N=118 women, PCOS. 152 cycles OPU day 9 -14 ET – 140 cycles Clinical pregnancy rate – 40% / transfer 56 livebirths and another 10 ongoing. Zhao et al, F&S, 2008

Summary –High responders IVF • The Gn. RH antagonist protocol appears to be an Summary –High responders IVF • The Gn. RH antagonist protocol appears to be an attractive option for PCOS patients undergoing IVF. • Ovulation triggering with Gn. RH-a may be a better option than cycle cancellation or prolonged coasting. • The addition of metformin to the treatment protocol may be beneficial for PCOS. • Pretreatment with an OCP may be beneficial.