This document discusses the management of poor or hyper ovarian response in IVF treatment. It covers topics such as predicting ovarian reserve, definitions of poor response, protocols for poor and hyper responders, and techniques like coasting to help prevent ovarian hyperstimulation syndrome. Coasting, where gonadotropin administration is stopped but down regulation continued, is an effective way to prevent OHSS while still allowing for embryo retrieval and transfer. GnRH antagonist protocols may also help lower the risk of OHSS compared to long agonist protocols. There is no single best protocol, and treatments should be individualized based on patient factors and expectations.

1. Management of Poor Or Hyper Ovarian response

2. Ovarian Reserve Every girl is born with a finite number of eggs, and their number progressively declines with age. A measure of the remaining number of eggs in the ovary is called the "ovarian reserve"; and as the woman ages, her ovarian reserve gets depleted.

3. No. of Primordial Follicles Erickson GF 2000, Adashi EY (ed) N. Y. 31-48 Gougheon A, (2004) in Leung PK et al., (ed) San Diego 25-43. No. of oocytes 7 th Month of gestation 7.000.000 At Birth 2.000.000 Age of seven year 300.000 Puberty 40.000 Released by ovulation 400 – 500

4. Prediction age History of previous poor response History of previous OHSS FSH Estradiol Inhibin anti-Müllerian hormone PCOS antral follicle count

5. Pregnancy rate

6. The use of a wide range of tests suggests that no single test provides a sufficiently accurate result

7. AMH If kits are available, AMH measurement could be the most useful in the prediction of ovarian response in anovulatory women. It is done at any day of cycle It is too expensive Exact normal levels not yet well agreed upon

8. During Induction? Careful monitoring of ovarian response: US E2

9. Poor Response No universal definition General consensus: women with poor response to ovarian stimulation OR those with low ovarian reserve

10. PREGNANCY RATE ACCORDING TO AGE AND NUMBER OF OOCYTES RETRIEVED

11. What is poor response in IVF Less than 5 follicles from both ovaries Oocyte quality is not related to number of oocytes but to women age Young women with poor response has good quality embryos and better chance of getting pregnant

12. LOW RESPONDERS CLASSIFICATION 1) Elderly patients with an abnormal endocrinological profile. 2) Young patients with an altered endocrinological profile. 3) Young patients with a normal basal hormonal profile.

13. What to do Increasing gonadotrophin in the same cycle does not result in significant improvement in the number of oocytes, embryos or pregnancies

14. Cancellation Is a very good option in this cycle Based on counselling the couples Decision to continue is still valid especially with advanced age (more than 38 years old women)

15. In subsequent cycles Increasing gonadotrophin in the subsequent cycle does not seem to result in significant improvement in the number of pregnancies obtained but may improve number of ooctes

16. What should be the maximum FSH dose in IVF/ICSI in poor responders 450IU/day

17. Protocols for IVF GnRH Antagonist Protocols GnRH Agonist Protocols 225 IU per day (150 IU Europe) Individualized Dosing of FSH/HMG 250  g per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe) Day 6 of FSH/HMG Day of hCG Day 1 of FSH/HMG Day 6 of FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1 FSH/HMG OCP

18. Protocols for poor responders Long protocol with large doses of gonadotropins Short protocol. Minidose of GnRH agonist protocol Clomiphene / hMG protocol Large doses of clomiphene protocol without hMG GnRH antagonist protocols.

19. GnRh antagonist protocol are associated with lower total dose and shorter duration of stimulation when compared with standard long protocol But no difference regarding pregnancy rate

20. Short (flare up protocol): GnRH-a is started on day one or two of the cycle. Exogenous FSH administration, then is started on day 3 of the cycle to continue follicular stimulation, meanwhile complete pituitary desensitization occur.

21. Ultra-short protocol GnRHa is given for only three days with the flare up technique LH could be suppressed till the mid cycle This protocol will help to retrieve more oocytes with a minimal risk of premature LH surge.

22. lower cancellation rates in the long protocol treatment group (versus stop and GnRHa flare-up protocols).

23. Growth hormone Growth hormone may improve the number of oocytes but no difference in pregnancy rate However, they are expensive and routine use can not be justified

24. NC Minimal stimulation and natural cycle protocols are gaining interests in low responders The have comparable results with standard IVF ovarian stimulation They are simple and cheaper

25. There is no single best protocol that can transform a low responder into a high responders The expectations should be discussed with the patients. It is preferable to opt for a simpler and less expensive regimen for ovarian stimulation (Sunkara et al, 2007)

26. the efficacy of natural cycle IVF is hampered by high cancellation rates mainly due to untimely LH surge

27. Poor response TI/IUI Gonadotrophins Modified natural cycle ” Antagonist “ IVM” IVF

28. Hyperresponse In its severest forms, it is complicated by hemoconcentration, venous thrombosis, electrolyte imbalance and renal and hepatic failure. Shenker and Weinstein, 1978; Navot et al., 1992; Aboulghar et al., 1993

29. Stop hMG and continue down regulation. This is the only complete prevention. (Navot et al., 1992; Rizk and Aboulghar 1999; Aboulghar and Mansour, 2003) Coasting: HCG dose and other alternatives Luteal phase : progesterone only.

30. Coasting is a routine practice at The Egyptian IVF-ET Center (May 2001 – May 2003) No. of Cycles 4969 No. of Coasting 560 Mean E 2 on hCG day 3742 + 1074 Days of Coasting 2 – 6 No. of Oocytes 18 + 7 No. of Cancelled ET (cryopreservation of all embryos) 3 OHSS (%) 6 (1.2 per 1000) Clinical Pregnancy (%) 265 (47.32%)

31. Coasting Clinical and practical aspects The Egyptian IVF-ET Center Experience When to stop gonadotropins? When the leading follicles reach 16mm how many days? Till the E2 drops to < 3000 pg/ml (Sher et al., 1995; Benavida et al., 1997; Tortoriello et al., 1998; Egbase et al., 1999; Fluker et al., 2000; Ohata et al., 2000) Dose of hCG? 5000 IU is enough Special laboratory aspects? Extra time to identify the oocytes from the follicular fluid

32. GnRH antagonist In a Cochrane review by Al-Inany , Abousetta and Aboulghar (2005) comparing agonist and antagonist, significant difference in the incidence of OHSS was found.

33. Novel Approach Coasting + Antagonist If E2 >6000 Pg/ml Reduce duration of coasting Extremely efficient Allow for continuing hMG at minimal dose Oocyte quality is high

34. THANK YOU