Managing poor responders in IVF

2. Managing poor responders in IVF Bye : DR Seyed Mehdi Ahmadi GYN & Gynecologist

4. Definition of ovarian poor responder: The definition of poor responders has varied throughout the medical literature . • Three or fewer oocytes or follicles . • Estradiol (E2) level below 500 pg/ml. • Fewer than five oocytes retrieved in high gonadotropin dose cycles (at least 450 inter national IU of FSH with a peak E2 below 1000 pg/ml . • Most literature on poor responders has utilized at least 450 IU of FSH, yet several studies in the 1990s confirmed no added benefit to gonadotropin dosing above 450 IU of hMG or FSH.

5. POR definition(ESHRE) • At least two of the following three features must be present: • Advanced maternal age (≥ 40 years) or any other risk factor for POR. • A previous POR (≤3 oocytes with a conventional stimulation protocol) • An abnormal ovarian reserve test (i.e. AFC = 5–7 follicles or AMH=0.5–1.1 ng/ml) )

6. Poor responders – how to diagnose E2 D2 FSH HMG AFC AMH OOCYTES FOLLICLES

7. Diagnosis: • Basal (day 3) FSH level • day 10 FSH level of the clomiphene citrate (CC) challenge test. • Serum basal FSH • Estradiol levels • anti-Müllerian hormone • Sonographic assessment of ovarian reserve including (ovarian volume & antral follicle count) • Color Doppler of ovarian However, the most accurate predictor of a poor response cycle is a history of poor response to gonadotropins.

8. Poor responders – BOLOGNA criteria from ESHRE ADVANCED AGE>40/OTHER RISK FACTORS FOR POR ABNORMAL ORT PREVIOUS POR

9. Poor responders – how to sight them? FSH Most commonly used Easily available D2 or D3 higher values –predictive False positive rate 5% SCREENING TEST! AMH Costly test Not widely available Cycle independent Better predictive value Current role - controversial AMH Costly test Not widely available Cycle independent Better predictive value Current role - controversial AFC Simple test Good inter- & intra- observer reproducibility Before starting stimulation Better correlation with retrieval number Current role – widely practised ultrasound

10. Poor responders – how to manage them? Mini dose protocol Conventional Agonists protocol - Dampening of ovarian response to gonadotropin stimulation Adjuvant therapy Modify Stimulation Protocol “Stop” protocol Short/ Ultra-short/Flare protocol Micro dose flare protocol

11. Poor responders – how to manage them? Antagonist protocol -decreases stimulation duration -fewer cancellations -lesser Gonadotropins Modify Stimulation Protocol

12. Poor responders – how to manage them? Growth Hormone Estradiol Adjuvant therapy Androgens COC pill Soft Protocols r- LH L-arginine, steroids, aspirin

13. Poor responders – how to manage them? Potentiates effect of FSH Previous poor responders have proven benefit Costly Not widely available No consensus on dose / route Growth Hormone Case – Control design 128 – 81 2U s/c Growth Hormone More M-II oocytes, higher E2 levels, pregnancy rates

14. Poor responders – how to manage them? Essential prohormone in follicular steroidogenesis Improves the ovarian micromilieu Micronised DHES – 25mg TID X 4months Improves pregnancy rates and reduces miscarriage rates Androgens DHES

15. Poor responders – how to manage them? • LH plays a role in follicular development • From D8, 75-150 IU • Beneficial in a subset of • a. age >35, • b. previous POR • c. Antagonist cycles • Improves pregnancy rates r- LH

16. Treatment(Is There an Ideal Protocol?) There is no really efficient treatment that could solve the problem of poor ovarian response and the current question is still which is the ideal protocol for patients defined as “poor responders”?

17. Gonadotropins : • It is confirmed that the increase of FSH starting dose , does not result in higher pregnancy rates . • It is found no differences between the starting dose of 300UI, 450UI, and 600 UI of gonadotropins in terms of retrieved oocytes,number of embryos obtained and pregnancy rates. • Maximal dosing, currently set at 450 IU of FSH, should be started as early in the cycle as possible. The dose may then be reduced once adequate response has been established.

18. HMG versus recombinant FSH • Recombinant FSH (rFSH) was introduced in the mid-1990s, and was initially touted to improve stimulation and pregnancy rates when compared with the already available equivalent dose of hMG. • More recent trials have suggested that hMG may have advantages for poor responders undergoing IVF, although the data are limited . • Mixed protocols of rFSH and hMG have become popular to provide both a high FSH dose as well as some LH activity.

19. The role of LH in stimulation protocols for poor responders • LH stimulation is available as both a recombinant LH (rLH) and in the standard urinary hMG, which contains a 1:1 ratio of FSH and LH activity. • Additional LH activity during stimulation for IVF can be obtained with low doses of urinary or recombinant hCG. • LH activity has been postulated to be beneficial during early follicular recruitment by increasing FSH receptors, as well as maintaining follicular development during later follicular maturation by maintaining steroid precursors.

20. Articles have looked at the role of LH, both recombinant as well as mixed protocols with hMG. • One reviewer has suggested that hMG, due to its LH activity, slightly increases the pregnancy rates in IVF when compared with rFSHalone. • Most reviews and meta- analyses of the role of LH, however, have been unable to confirm any benefit or detriment of LH to IVF pregnancy or LBRs.

21. GnRHAnalogues : in poor ovarian reserve the options could be : • To decrease the length of suppression by decreasing the duration of GnRH agonist use (short and ultrashort, mini- and microdose flareup regimens) .

22. 1.GnRH agonist microdose flare protocols : • It has been shown that a single dose of 25–50 µg of GnRH agonist given on cycle day 2 can increase both FSH and LH levels. • The protocols utilizing minimal doses of GnRH agonists such as 20–50 µg twice daily (b.i.d.) for 2 days at the beginning of the cycle (microdose flare protocols) are usually combined with OCP pretreatment in the cycle prior to COH to prevent corpus luteum rescue .

23. In retrospective studies: the use of microdose protocols in poor responders has shown improved cycle outcome with regards to the number of retrieved oocytes, percentage of patients undergoing embryo transfer, cancellation rates and pregnancy rates, when compared with traditional long GnRH agonist protocols.

24. 2.GNRH antagonist: Advantages of the use of GnRHantagonist + gonadotropins are : • Improvement of patient’s compliance. • Decreased number of days of stimulation and of the amount of gonadotropin administered. • Reduction of ovarian hyperstimulationsyndrome (OHSS). • GnRH antagonists are not administered during the stage of follicular recruitment and thus suppression of endogenous gonadotropins secretion is not present at that time . • Most protocols commence GnRH antagonists when the mean diameter of the lead follicle reaches 14 mm and continue daily until human chorionic gonadotropin (hCG) administration.

25. suitable protocol for poor responders: GnRHantagonists + gonadotropins Reason : GNRH antagonists in the mid-late follicular phase during ovarian stimulation prevent the premature LH surge while not causing suppression in the early follicular phase, obtaining more natural follicular recruitment without any inhibitory effect possibly induced by theGnRH agonist.

26. As a general : Employ flare protocols when using OCPs and Antagonist protocols when not pretreating with OCPs.

27. Clomiphene flare protocols • A flare of endogenous gonadotropins can be also achieved with early CC administration. In these cycles, endogenous LH surge can be blocked with GnRH antagonists . • CC flare was shown to: • Reduce cancellation rates • Increase the number of oocytes retrieved • Result in a higher implantation rate • Higher pregnancy rates in poor responders.

28. Concerns about The use of a CC flare : Endometrial suppression • CC is commonly and successfully used both in minimal stimulation protocols and for its flare effect in high-dose protocols in poor responders who are undergoing freeze-all cycles. • Its potential for negative endometrial effects during a fresh transfer cycle necessitates further study.

29. Letrozole flare protocols • Letrozoleis a highly selective aromatase inhibitor that has been used in assisted reproductive technology. • Mechanism: Blocking estrogen synthesis and decreasing its circulating levels →effect on the pituitary →increasing release of endogenous gonadotropins.

30. In COH protocols : letrozole doses of 2.5–5.0 mg daily on day 3–7 of stimulation cycle + menotropins + GnRHantagonist. • Addition of letrozolein poor response cycles can decrease the total dose of FSH used when compared with a long GnRH agonist protocol + having an advantage in antagonist cycles in poor responders.

31. Dosing intervals for poor responders • It has become common to offer b.i.d. dosing of hMG or FSH in poor responders. • When using mixed protocols of hMG from vials and rFSH from a pen, the authors often recommend twice-daily injections . • Despite no documented benefit from b.i.d. dosing, it continues to be popular, especially for mixed protocols in poor responders.

32. Minimal stimulation • Many studies have suggested that for poor responders, natural cycle IVF or IVF with minimal stimulation produces similar pregnancy rates as with full-dose gonadotropins . • A significant problem with natural cycle IVF is the high cancelation rate; however, use of GnRH antagonists in the late follicular phase has shown promising results .

33. Natural, clomiphene or letrozole only IVF • One randomized trial showed that poor responders treated with natural cycles + ICSI had higher implantation rates but similar clinical pregnancy rates per cycle and per transfer as patients treated with full-dose gonadotropins . • CC stimulation alone was far more successful than natural-cycle IVF. • Letrozole has also been looked at as an adjuvant in minimal stimulation cycles employing a low dose of gonadotropins.

34. Laboratory options in poor response cycles ICSI for low oocyte yield • Poor responders typically produce fewer than five oocytes per retrieval. • In couples with poor ovarian response and fertilization failure, ICSI could have a potential advantage over IVF.( Higher fertilization rate ). • If either the oocytes appear immature, or the mature-appearing oocyte is immature after stripping, employing standard IVF for the remaining oocytes. • An oocyte is considered immature when it is surrounded by corona radiata with a less dense cumulus oophorus.

35. Preimplantation genetic screening for poor responders ( PGD ) • Couples are at an increased risk of developing chromosomally abnormal embryos after unexplained repeated IVF failures or advanced maternal age . • Therefore, preimplantation genetic screening (PGS) utilizing FISH has been studied for patients with : • advanced maternal age • repeated miscarriage • repeated implantation failure • severe male factor infertility

36. Ideal day of transfer • In poor responders where fewer oocytes and embryos are available for transfers, transferring embryos at an earlier cleavage stage appears to be beneficial. • As a general rule, once the number of viable embryos is equal to the number planned to be transferred, further delay of transfer is likely to be more harmful than beneficial. • The clinical pregnancy rates per oocyte retrieval and per embryo transfer were significantly higher in the day 2 embryo transfer group compared with day 3.

37. Number of embryos for transfer • Indication for increasing the number of embryos to transfer: • advanced reproductive age • poor ovarian reserve • poor response • ASRM guidline: • in women aged less than 35 years→→→ up to two embryos • in women aged less than 38 years→→→ up to three embryos • in women aged less than 41 years→→→ up to four embryosEven in poor responders.

38. Donor oocytes • Recommend oocyte donation IVF only for: • poor responders with multiple failed IVF cycles • those with a very poor prognosis prior to IVF. • Very poor prognosis group includes : • all patients over 43 years of age • any patient with an FSH over 15 mIU/ml • an undetectable AMH.

39. Number of newer procedures in ART that have a role in the management of poor responders: • In vitro maturation (IVM) • Cryopreservation of oocytes • Embryos from multiple retrieval cycles • Cryopreservation of donor oocytes (egg banking )

40. Oocyte banking: • The use of cryo-banked oocytes in an ovum donation program may be a realistic option in the future, significantly increasing the efficiency of the donor process. • The process of synchronizing the recipient with the donor has some drawbacks, including waiting lists and coordinating recipient schedule to the timing of the donor.

41. Alternative Approaches

42. 1.DHEA TO IMPROVE OVARIAN FUNCTION

43. 2.Pre conditions the ovary for ovulation induction

44. ACTION OF DHEAS PROHORMONE IMPROVES REDUCES OVARIAN APOPTOSIS RESERVE IMPROVES AUGMENTSOVARIAN IGF -1 ENVIRONMENT DHEA

45. 1)Dehydroepiandrosterone (DHEA) • The mechanism by which DHEA supplementation may increase oocyte yield in poor responders is unknown. 1- Animal models support the theory that androgens might facilitate the response of the growing follicles to FSH. 2-In humans, this may result in higher AFC in patients with higher ovarian androgen levels such as in patients with polycystic ovary syndrome. It can also be responsible for the exaggerated ovarian response to exogenous gonadotropins in COH.

46. 3-Other theories include an increase of IGF-1 during gonadotropin stimulation, and improved follicular steroidogenesis . 4- In some studies, higher baseline testosterone levels were found to be associated with a higher number of oocytes retrieved and improved IVF outcomes . Older patients have been shown to have diminished levels of DHEAs and may benefit from achieving normal serum levels . 5-It has also been postulated that DHEA supplementation reduces follicular apoptosis, thereby increasing the pool of primordial follicles.

47. 2)Simple cyst drainage prior to stimulation protocols : • One of the most significant side effects of pituitary down regulation with GnRH agonists in COH protocols is ovarian cyst formation. • The incidence of these cysts ranges from 8 to 53% . • Formation of follicular cysts may be related to the endogenous gonadotropin flare in response to mid-luteal GnRH agonists. • The impact of these ovarian cysts on IVF outcomes remains controversial.

48. There is evidence of poor IVF performance in patients who form ovarian cysts in response to GnRH agonists in both poor responders and normal responders. • The worst outcomes were found with: Hormonally inactive cysts greater than 15 mm . • While follicular cyst formation prior to IVF is probably a poor prognosticator, further studies are required to determine whether to proceed, wait or drain the cyst prior to the cycle.

49. 3)Addition of Estradiol in the Luteal Phase Addition of estradiol in the luteal phase ± GnRHantagonist →→→Decreases the risk of cycle cancellation & Increases the chance of clinical pregnancy in poor responder REASON: luteal estradiol priming could improve synchronization of the pool of follicles available to controlled ovarian stimulation.