1. GnRH-a to trigger ovulation should be used in all PCOS patients to prevent OHSS Dr. Shahar Kol

2. Disclaimer The following presentation reflects my own experience and opinion. The presentation does not necessarily reflect drug companies’ policies. I mention off-label use of medications, this use is not endorsed by drug companies.

3. IVM This option is thoroughly discussed in this meeting. If you adopt IVM you need not worry about OHSS. If you choose to stimulate your PCOS patient, please use the GnRH antagonist option. Mild stimulation is a great idea, not easy to implement.

4. AUGUST 2009 VOL 5 NO 8 AUGUST 2009 AUGUST 2009 VOL 5 NO 8 If you choose a long GnRH agonist protocol, this what might happen

5. Basic clinical details 25-year-old, 2 years of primary infertility Irregular cycles, facial hair BMI=24, LH=14.9, Testo=2.5, FSH-normal US: PCOS Impaired glucose tolerance – started Metformin 850 twice daily Sperm-normal FSH-normal

6. Pre-IVF treatment CC up to 100 mg daily – no ovulation 5 cycles with recFSH 50 U daily. Four cycles mono-ovulation, 1 cycle cancelled for multifollicular development. No pregnancy. Referral to IVF.

7. IVF – cycle I Long agonist protocol, continue metformin, daily gonadotropin dose of 112.5 U – no response, increase to 150 U – good response Trigger with hCG 10,000 U OPU: 16 eggs from 20 follicles. ET: 2 embryos, no pregnancy.

8. IVF-cycle II Same long protocol, continue metformin, starting dose 150 U. After 7 days: “unfortunately” 25 follicles<12 mm, 9 follicles 13-16 mm, dose reduced to 125 U, trigger with hCG 5,000 U. OPU: 41 eggs, 21 embryos frozen. 2 days later: abdominal pain, vomiting. US: large ovaries. Hemoglobin -16.3, WBC-31,700. Decision to hospitalize.

9. In hospital IV fluid (crystaloid), enoxaparin 40mg Poor urinary output, albumin i.v Fluid balance +1,500 in 24 h. Chest X-ray: pleural effusion

10. Getting worse Chest and abdominal drains. During 24h 2 L of ascitic fluid and 1 L pleuritic fluid was drained. Further deterioration: O 2 sat <95%, X-ray: bilateral pleural effusion and pulmonary edema.

11. ICU Risk of adult RDS – transferred to ICU 2 nd chest tube inserted Central i.v. line Continue albumin Gradual improvement and discharge after a few days.

12. Severe OHSS: is it still a problem? “In 2003–2005, 4 deaths (of the 12) were due to OHSS” ~3 OHSS-related deaths per 100,000 ART cycles Year Deaths 95% CI Number of treatment cycles NumberRate 1997– 19992019.1712.41–29.61104,320 2000–200287.323.71–14.44109,308 2003–20051210.085.76–17.61119,080 * Source Human Fertilisation and Embryology Authority Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005

13. Three OHSS-related deaths (3:100,000), all had their embryos frozen Braat DDM, et al. Hum Reprod 2010;25:1782–1786

14. Youssef MA, et al. Human Reprod Update 2010;16:459–466 What really works: ●GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles

15. 16 publications Agonist: 2005 patients, not a single case of OHSS! hCG: 92 cases in 1810 patients, 5.1%

16. The physiology of agonist trigger 1.Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print); 2.Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922 LH surge 1 FSH surge 2

18. What happens after agonist trigger? Complete luteolysis! Luteal phase Natural cycle Day 7–9 = 75 pg/mL vs 18 Natural cycle Day 7–9 = 750 pg/mL vs 84 Nevo O, et al. Fertil Steril 2003;79:1123–1128

20. “The concept of an OHSS-Free Clinic has become a reality. This approach should include pituitary down-regulation using a GnRH antagonist, ovulation triggering with a GnRH agonist and vitrification of oocytes or embryos” “…luteal phase supplementation with low-dose hCG has to be fine tuned.” Devroey P, et al. Human Reprod 2011; 26: 2593–2597

21. OHSS prevention by GnRH agonist triggering of final oocyte maturation in a GnRH antagonist protocol in combination with freeze-all strategy: a prospective multicenter study Conclusions: “…a single case of a severe early onset OHSS occurred” – E 2 trigger day=47,877 pmol/L – 13 oocytes – The patient was hospitalized on day of OPU, with abdominal distension, drastically enlarged ovaries (right and left ovarian volume 363 cm 2 and 261 cm 2, respectively), and lower abdominal pain. – She received low molecular weight heparin, cabergoline (0.5 mg/d), and IV infusion therapy, including albumin. Griesinger G, et al. Fertil Steril 2011;95:2029–2033 Failures?

22. Failures? (cnt’d) – “drastic decrease of hemoglobin levels to 4.9 mmol/L” (8 grams/dL) patient received blood transfusion 2 days post OPU. – Hematocrit: 41 trigger day, 37 OPU day, ‘,<35’ post blood transfusion. – 3–4 days post trigger 3.9 litres of “blood-stained ascites which was indicative of a subacute intraperitoneal hemorrhage”.

23. How to secure good clinical outcome post agonist trigger? High risk fresh transfer: intensive E 2 +P luteal support High risk: ‘freeze-all’ Low risk: luteal rescue based on LH activity

24. Luteal phase: intensive E+P OHSS high-risk patients Study groupControl groupOdds ratio (95%CI)p value Primary end points OHSS (ITT) Total, n (%)0/33 (0)10/32 (31.3)0 (0–0.26) a <0.01 Moderate/severe, n (%)0/33 (0)5/32 (15.6)0 (0–0.74) a 0.02 OHSS (PP) Total, n (%)0/30 (0)10/2 (34.5)0 (0–0.26) a <0.01 Moderate/severe, n (%)0/30 (0)5/29 (17.2)0 (0–0.73) a 0.02 Secondary end point (PP) Implantation rate, n (%)22/61 (36)20/64 (31)1.18 (0.52–2.65)0.69 Other end points (PP) Positive pregnancy, n (%)19/30 (63.3)18/29 (62.1)1.06 (0.37–3.0)0.92 Clinical pregnancy rate, n (%)17/30 (56.7)15/29 (51.7)1.22 (0.4–3.4)0.45 Ongoing pregnancy rate, n (%)16/30 (53.3)14/29 (48.3)1.22 (0.4–3.4)0.45 a The estimates of these odds ratios are zero, because no patient developed OHSS in the study group; ITT=intention to treat; PP=per protocol Engmann L, et al. Fertil Steril 2008;89:84–91

25. GnRHa Trigger and Total Freeze in High Risk Patients Griesinger et al., 2007, observational, 20 high- risk patients (≥ 20 follicles ≥ 11mm) - cumulative ongoing pregnancy rate 37 % Griesinger at al., 2011, observational, 51 high-risk patients (≥ 20 follicles ≥ 11mm) - cumulative live bith rate 37 %

26. The advantage for the ‘normal responder’ Kol S, et al. Human Reprod 2011;26:2874–2877 FSH/hMG Antagonist Agonist trigger 36 hours OPU 1500 IU hCG 4 days 1500 IU hCG ET

27. Stimulation characteristics and embryology data Stimulation (days)9.3 ± 2.0 GnRH antagonist (days)3.8 ± 0.9 FSH (units)2443 ± 925 E 2 day of trigger (pmol/L)3764 ± 1227 P day of trigger (nmol/L)2.4 ± 1.65 LH day of trigger (IU/L)1.9 ± 1.3 Oocytes retrieved6.7 ± 2.5 Embryos obtained3.6 ± 1.7 Embryos transferred2.9 ± 0.9 Embryos frozen0.8 ± 1.5 Beta hCG (IU/L)152 ± 86 E 2 (day of pregnancy test, pmol/L)6607 ± 3789 P (day of pregnancy test, nmol/L)182 ± 50 Values are mean ± SD Reproductive outcomes Positive hCG/cycle, n (%)11/15 (73) Clinical ongoing pregnancy, n (%)7/15 (47) Early pregnancy loss, n (%)4/11 (36) Kol S, et al. Human Reprod 2011;26:2874–2877

28. Side benefits Agonist trigger: more MII oocytes compared with hCG trigger 1-4 Potential benefit of FSH surge: 5-9 – Promotes LH receptor formation in luteinizing granulosa cells – Promotes nuclear maturation (i.e. resumption of meiosis) – Promotes cumulus expansion 1.Humaidan P, et al. Reprod Biomed Online 2005;11:679–684 2.Humaidan P, et al. Human Reprod 2009;24:2389–2394 3.Imoedemhe DA, et al. Fertil Steril 1991;55:328–332 4.Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5.Eppig JJ. Nature 1979;281:483–484 6.Strickland and Beers. J Biol Chem 1976;251:5694–5702 7.Yding Andersen C. Reprod Biomed Online 2002;5:232–239 8.Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731 9.Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666

29. Anecdotal cases You may consider GnRH agonist trigger in the following cases: – Repeated IVF failure – “empty follicles” syndrome – Immature oocytes despite adequate follicular diameter

30. Crystal ball: where are we heading? OutIn ‘Long agonist’ protocolsAntagonist-based protocols hCG triggerAgonist trigger 1–2% severe OHSSTotal OHSS elimination OHSS-related death rate: 3:100,000Total OHSS elimination