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GnRH-a to trigger ovulation should be used in all PCOS patients to prevent OHSS

GnRH-a to trigger ovulation should be used in all PCOS patients to prevent OHSS. Dr. Shahar Kol. Disclaimer. The following presentation reflects my own experience and opinion. The presentation does not necessarily reflect drug companies’ policies.

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GnRH-a to trigger ovulation should be used in all PCOS patients to prevent OHSS

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  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 2009VOL5NO8 AUGUST 2009VOL5NO8 AUGUST 2009VOL5NO8 AUGUST 2009  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: O2 sat <95%, X-ray: bilateral pleural effusion and pulmonary edema.

  11. ICU • Risk of adult RDS – transferred to ICU • 2nd 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? Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005 • “In 2003–2005, 4 deaths (of the 12) were due to OHSS” • ~3 OHSS-related deaths per 100,000 ART cycles

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

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

  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 LH surge1 FSHsurge2 Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print); Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922

  17. 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

  18. “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

  19. Failures? 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” • E2 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 cm2 and 261 cm2, 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

  20. 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 subacuteintraperitoneal hemorrhage”.

  21. How to secure good clinical outcome post agonist trigger? • High risk fresh transfer: intensive E2+P luteal support • High risk: ‘freeze-all’ • Low risk: luteal rescue based on LH activity

  22. Luteal phase: intensive E+POHSS high-risk patients Engmann L, et al. Fertil Steril 2008;89:84–91

  23. 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 %

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

  25. Kol S, et al. Human Reprod 2011;26:2874–2877

  26. Side benefits • Agonist trigger: more MII oocytes compared with hCG trigger1-4 • 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 Humaidan P, et al. Reprod Biomed Online 2005;11:679–684 Humaidan P, et al. Human Reprod 2009;24:2389–2394 Imoedemhe DA, et al. Fertil Steril 1991;55:328–332 Oktay K, et al. Reprod Biomed Online 2010;20:783–788 Eppig JJ. Nature 1979;281:483–484 Strickland and Beers. J Biol Chem 1976;251:5694–5702 Yding Andersen C. Reprod Biomed Online 2002;5:232–239 Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731 Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666

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

  28. Crystal ball: where are we heading?

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