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ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES

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ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES

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ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES

  1. 1. ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES Muammer DOGAN, Assoc. Prof. MD
  2. 2. ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES <ul><li>Natural cycle </li></ul><ul><li>Hormon Controlled cycle </li></ul><ul><ul><li>-> GnRH-a programmed with E2 and P administration </li></ul></ul><ul><ul><li>-> Non GnRH-a programmed with E2 and P administration </li></ul></ul>
  3. 3. Natural Cycles in Frozen ET <ul><li>Women with regular cycles </li></ul><ul><li>In ovulatory cases, frozen ET is successfully carried out after spontaneous ovulation. </li></ul><ul><li>Cohen 1988, Testart 1988, Muasher 1991, Loh SKE 1999. </li></ul><ul><li>Is cheaper. </li></ul><ul><li>May be used in young cases. </li></ul><ul><li>It is not the proper option when better control and flexibility in timing is desired . </li></ul>
  4. 4. Natural Cycles in Frozen ET <ul><li>It requires endogenous hormone production. </li></ul><ul><li>Ovulation time must be identified clearly. This may cause anxiety. </li></ul><ul><li>Cancel rate 6% </li></ul><ul><li>(Sathanandan 1991) </li></ul><ul><li>After 35 (Queenan 1995) and 40 (Al-Shawaf 1993), fecundity with natural cycle is decreased in frozen ET. </li></ul>
  5. 5. Natural Cycles in Frozen ET <ul><li>It can not be used in menstrual irregularity. </li></ul><ul><li>In many ART patients, anovulation,irregular cyles,the presence of PCOS and LPD prevents clear determination of ET time. For this purpose, the use of CC and hMG is on the agenda. Cohen;1988 </li></ul><ul><li>The adverse effect of CC on endometrium, potential side effects of hMG caused the transfer to the presently used protocols in all cases. </li></ul>
  6. 6. Natural Cycles in Frozen ET <ul><li>4 days before ovulation monitorization in ~ D8- D10 </li></ul><ul><li> (USG, E2, LH, P) </li></ul><ul><li>DF › 14 mm LH measurement </li></ul><ul><li>2 days after ovulation ( DF loss in USG, 2SD increase from the basal in P ) and 3 days after LH peak -> ET </li></ul><ul><li>Progesteron support is not usually required. Sometimes P may be given for luteal support. </li></ul>
  7. 7. <ul><li>Frozen- thawed embryos can be transferred to naturally cycling women or to women who have been primed with hormone replacement treatment with equal succes. </li></ul><ul><li>Byrd W Semin Reprod Med 2002;20:37 . </li></ul>
  8. 8. Hormonally Manipulated Cycles in Frozen ET <ul><li>In cases whose ovary is functional but who have anovulatory and irregular cycles , frozen ET should be carried out only after adequate endometrial preparation. </li></ul><ul><li>In these cases, ovulation may be induced by CC or hMG or ET may be performed after ovulation. </li></ul><ul><li>Van der Auwera;1994. </li></ul>
  9. 9. Hormonally Manipulated Cycles in Frozen ET <ul><li>The fact that adequate endometrial preparation can be carried out with exogenous hormone administration was originially demonstrated by Navot et al. Navot;1989 </li></ul>
  10. 10. Hormonally Manipulated Cycles in Frozen ET <ul><li>It was shown that after GnRH-a down regulation, in cases with functional ovary, exogenous steroids could enable adequate endometrial preparation, simulating nonfunctional ovary donation cycles. </li></ul><ul><li>Muasher 1991, Younis 1996 </li></ul><ul><li> Devroey 1998 </li></ul>
  11. 11. Hormonally Manipulated Cycles in Frozen ET <ul><li>GnRH-a Employment </li></ul><ul><ul><li>Advantages </li></ul></ul><ul><ul><li>It simplifies the synchronization between embryo and endometrial development. </li></ul></ul><ul><ul><li>(E.g;anovulation and irregular cycle) </li></ul></ul><ul><ul><li>It decreases the need for USG and endocrine monitorization </li></ul></ul><ul><ul><li>The rate of cancellation decreases. </li></ul></ul><ul><ul><li>Transfer time is more readily controlled. </li></ul></ul><ul><ul><li>Smitz 1992, Keltz 1995. </li></ul></ul>
  12. 12. Hormonally Manipulated Cycles in Frozen ET <ul><ul><li>GnRH-a employment </li></ul></ul><ul><ul><li>Disadvantages </li></ul></ul><ul><ul><li>-Hypoestrogenic structure </li></ul></ul><ul><ul><li>-Paradoxal development </li></ul></ul><ul><ul><li>-Cyst formation </li></ul></ul><ul><li>-The need for maintaining daily exogenous hormone replacement throughout first trimester in pregnancy </li></ul><ul><li>-Prolongation of the duration of treatment. Smitz 1992, Keltz 1995. </li></ul>
  13. 13. Hormonally Manipulated Cycles in Frozen ET <ul><li>GnR-a, is necessary for sufficient endometrial hormonal manipulation in anovulatory frozen ET cases with functional ovary. </li></ul><ul><li>Meldrum DR 1989, Remohij 1995, </li></ul><ul><li>Younis JS 1996, El-Toukhy T;2004. </li></ul><ul><li>The employment of GnRH-a for controlled endometrial preparation in recipients with functional ovaries in frozen ET programs is not necessary . </li></ul><ul><li>de Ziegler D 1991, Pattison HA 1992, Yen B 1995, Queenan JT 1997, Simon A 1998, Oborna I 2004. </li></ul>
  14. 14. Hormonally Manipulated Cycles in Frozen ET <ul><li>E can be given, </li></ul><ul><li>Orally, transdermally, vaginally, s.c </li></ul><ul><li>P can be given </li></ul><ul><li>Orally, IM, vaginally, nasally, rectally, sublingually </li></ul><ul><li>The best route of administration of E and P in preparation for ET is unclear . </li></ul>
  15. 15. <ul><li>In endometrial preparation in Frozen ET cases, there is no difference between sublingual P (3x400mg) and parenteral P </li></ul><ul><li>(P in oil 50mg/g) with regard to IR. </li></ul><ul><li>Dale WS; 1996. </li></ul>
  16. 16. <ul><li>Vaginal P (%8 Crinone) V </li></ul><ul><li>İ.M P (100 mg) </li></ul><ul><li>Endometrial preparation was determined to be enough in all cases. </li></ul><ul><li>Patient compliance is better with vaginal use. </li></ul><ul><li>(less feeling of pain and discomfort) </li></ul><ul><li>There is no difference in the rate and maintainance of pregnancy. </li></ul><ul><li>Gibbons W;1998. </li></ul>
  17. 17. <ul><li>In programmed frozen ET, combined oral E2 and vaginal P employment is an effective, simple and inexpensive approach. There is no stastistically significant difference between IM and vaginal route in terms of P yield. Lightman A;1999. </li></ul>
  18. 18. <ul><li>The Estraderm TTS 100/Crinone 8% protocol seems to be superior to stimulation protocols and even to other protocols reported so far for artificial cycles with exogenous oestradiol and progesterone treatment. </li></ul><ul><li>Bals-Pratch; 1999. </li></ul>
  19. 19. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li>D2(Follicular) V D21(Luteal) </li></ul><ul><li>GnRH-a 10-14 days </li></ul><ul><li>(Buserelin 500mcg, Nafarelin 2x2/g, Triptorelin 3.75 mg or 0.1mg/g,LA 0.5mg/d.) </li></ul><ul><li>If Down regulation </li></ul><ul><li>(P‹ 0.5ng, E2 ‹50pg, LH ‹ 5 mIU) did not occur, treatment is maintained for one more week and values are repeated </li></ul><ul><li>After down regulation, the duration of proliferative phase which will last until the commencement of progesteron is approximately 12-20 days. </li></ul>
  20. 20. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li>HRT is initiated after down regulation. </li></ul><ul><li>D1-D8 E2 Valerat or micronized E2 </li></ul><ul><li> 2 mg </li></ul><ul><li>D9-D11 4 mg </li></ul><ul><li>D12 6 mg </li></ul><ul><li>D14 USG End > 8mm Luteal support </li></ul><ul><li>Micronised P 2x400mg vaginal cap. </li></ul><ul><li>Crinone 8% (90 mg) vaginal gel Cylogest 400 mg vag.tab 2X1 </li></ul>
  21. 21. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li>D16-17 ET </li></ul><ul><li>(48-72 hours after P ) </li></ul><ul><li>After ET 14 day β -hCG </li></ul><ul><li>If pregnancy is present E2 8 mg and P at the same or twofold dose is administered until placental autonomy . </li></ul><ul><li>Porcu E;1997. </li></ul>
  22. 22. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li>Transdermal E2 </li></ul><ul><li>(Estraderm TTS 100) </li></ul><ul><li>(Patch should be changed every two days) </li></ul><ul><li>After Down regülasyon; (e.g.;LA 0.5mg/g sc) </li></ul><ul><li>D1-D8 E TTS 0.1 mg </li></ul><ul><li>D9-D10 E TTS 0.2 mg </li></ul><ul><li>D11-D12 E TTS 0.3 mg </li></ul><ul><li>D13-D14 E TTS 0.4 mg </li></ul><ul><li>D15 -> E TTS 0.2 mg </li></ul><ul><li>Luteal support P İn oil 50mg IM. LA is discontinued. </li></ul>
  23. 23. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li>D17 ET </li></ul><ul><li>After ET, 14th day β -hCG </li></ul><ul><li>If pregnancy is present, E2 ve P dose administered until placental autonomy. </li></ul><ul><li>Muasher;1991 </li></ul>
  24. 24. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li>D1 Mikronised 17 β E2(Estrafem) 4mg/g 2x1 </li></ul><ul><li>D7 E2, P, USG measurement </li></ul><ul><li>E2 < 800pmol/L or </li></ul><ul><li>End < 8mm </li></ul><ul><li>Dose 6-8 mg/d is maintained for 5-10 more days </li></ul><ul><li>End≥8mm Luteal support </li></ul><ul><li>Mikronised P 3x300mg Vag . </li></ul><ul><li>S imon A;1998 </li></ul><ul><li>(First controlled randomized study ) </li></ul>
  25. 25. Hormonally Manipulated Cycles in Frozen ET ( GnRH-a Programmed) <ul><li> 48-72 hours after P ET </li></ul><ul><li>After ET 14th day β -hCG </li></ul><ul><li>If pregnancy is present, this dose is given until placental autonomy </li></ul><ul><li>S imon A;1998 </li></ul><ul><li>(First controlled randomized study) </li></ul>
  26. 26. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) <ul><li>D1 Mikronised E2 Estrafem(6mg/d 3x1 p.o) </li></ul><ul><li>(In previous schemes 2mg/d Pattison;1992, Queenan;1997.) </li></ul><ul><li>(Today, E2 treatment is started on cyle day 25 of the previous cycle) </li></ul><ul><li>The aim of high dose E is supression of gonadotropic cells, follıculogenesis and the prevention of LH peak.) </li></ul><ul><li>D7 E2, End. thickness (End ≥8mm) </li></ul><ul><li> Luteal support (Mic.P 3x300mg vaginal) </li></ul><ul><li>(D7 – Luteal sup. P ≥6nmol/L V </li></ul><ul><li>D20 End. thickness < 8 mm cycle cancellation) </li></ul><ul><li> Simon A;1999. </li></ul>
  27. 27. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) <ul><li>48-72 hours after P -> ET </li></ul><ul><li>14th day after ET-> β -hCG </li></ul><ul><li>If pregnancy is present, this dose is given until placental autonomy. </li></ul><ul><li>The rate of cancellation is low, </li></ul><ul><li>The probability of premature P secretion is small. </li></ul><ul><li>Conclusion : 6mg/d Mic. E2, gonadotropin secretion is sufficient for prevention of spontaneous ovulation and endometrial preparation. </li></ul><ul><li>Simon A;1999. </li></ul>
  28. 28. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) <ul><li>Serum E2 level is unimportant in decision for ET. Only one serum P level measured with USG when starting P is enough for decision. </li></ul><ul><li>If endometrial thickness is adequate and premature P secretion is absent, P support may continue after ET. </li></ul><ul><li>Simon A;1999. </li></ul>
  29. 29. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) <ul><li>D1 4mg/g E2 Valerate </li></ul><ul><li>D14 P measurement (for spontaneous ovulation) </li></ul><ul><li>(p›0.9 ng/ml cycle cancellation) </li></ul><ul><li>D15 Mic.P 300mg/g vaginal </li></ul><ul><li>D19 ET </li></ul><ul><li>D29 β -hCG </li></ul><ul><li>If pregnancy is present, E2 and P dose x2 is maintained until placental autonomy. </li></ul><ul><li>Lelaider C; 1995. </li></ul>
  30. 30. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) <ul><li>The high PR observed after transferring blastoctsts on the 5th day of endometrial exposure to P in controlled E2 and P replacement cycles. </li></ul><ul><li>Lelaider C; 1995. </li></ul>
  31. 31. Hormonally Manipulated Cycles in Frozen ET ( Non GnRH-a Programmed) <ul><li>Endometrial preparation with exogenous E and P without GnRH-a is simple, easy and efficient in frozen ET cases with active ovary. </li></ul><ul><li>Jaroudi;1991, </li></ul><ul><li>Pattison HA;1992, </li></ul><ul><li>Lelaider C; 1995, </li></ul><ul><li>Queenan JT;1997, </li></ul><ul><li>Simon A; 1999, </li></ul><ul><li>Dal Prato L;2002, </li></ul>
  32. 32. <ul><li>It seems to be appropriate to start progesterone administration before transfer in oocyte donation programmes as well as transfer of cryopreserved / thawed cell as soon as the endometrium is developed sufficiently (8mm,trilaminar pattern), and to perform the embryo transfer not before day 3 - 4 of progesterone treatment, i.e. embryo development on day 2-3. Nawroth F;2005. </li></ul>
  33. 33. Retrospective Analysis <ul><li>A. LA + Transdermal E2 patch </li></ul><ul><li>B. LA + Oral Mic. E2 </li></ul><ul><li>C. Oral Mic. E2 </li></ul><ul><li>Down regulation with GnRH-a is not necessary. Regimes not programmed with GnRH- are simple and more economical. Yee;1995. </li></ul>
  34. 34. <ul><li>A. Naturel cycle </li></ul><ul><li>(Luteal P support) </li></ul><ul><li>B. Artificial preparation (GnRH-a + E2 + P) </li></ul><ul><li>C. Ovarian Stimulation (GnRH-a + hMG + hCG + P) </li></ul><ul><li>Thre is no significant difference in terms of IR . </li></ul><ul><li>Vasilios T;1996, Tanos V; 1996. </li></ul>
  35. 35. <ul><li>A- 400 mcg buserelin acetate + 6 mg E2 valerate + </li></ul><ul><li>(800 mg/d P) </li></ul><ul><li>B- 6 mg E2 valerate </li></ul><ul><li>(800 mg/d P) </li></ul><ul><li>Medicated frozen embryo replacement cycles timed by endometrial thickness measurement alone without monitoring or suppression of ovarian activity are associated with reduced outcome. </li></ul><ul><li>El-Toukhy T;2004. </li></ul>
  36. 36. In Frozen EmbryoTransfer; <ul><ul><li>Significant effect - </li></ul></ul><ul><ul><li>Patient age , number of embryos replaced </li></ul></ul><ul><ul><li>No significant effect - </li></ul></ul><ul><ul><li>Duration of storage of embryos </li></ul></ul><ul><ul><li>Stimulation type </li></ul></ul><ul><ul><li>Cause of infertility </li></ul></ul><ul><ul><li>( Avery and Brinsden;1997) </li></ul></ul>
  37. 37. <ul><li>Embryo quality evaluated morphologically was the most important clinical factor for succesful implantation of cryopreserved- thawed ET. </li></ul><ul><li>Kondo I;1996. </li></ul>
  38. 38. <ul><li>Good quality of frozen thawed embryos and the trilaminar sonographic pattern of endometrium may be reliable predictors of success in pregnancy. Zhu Y;2001 . </li></ul>
  39. 39. <ul><li>For thin endometria, </li></ul><ul><li>there was not a observed trend suggesting lower PRs. </li></ul><ul><li>Jerome HC;2004. </li></ul>
  40. 40. <ul><li>Neither the mode of endometrium preparation nor the length of cryostorage appears to affect the outcome of frozen ET cycles. </li></ul><ul><li>Kolibianakis EM;2003. </li></ul><ul><li>The type and administration route of the steroid form has no effect on the success of the frozen ET cycles. </li></ul>
  41. 41. CONCLUSION- I <ul><li>Endometrial preparation is cheaper with natural cycles. </li></ul><ul><li>It can not be used in menstrual irregularity. </li></ul><ul><li>Therefore, it should be preferred in younger cases. </li></ul><ul><li>It is not a suitable choice when better control and fleixbility in timing is desired. </li></ul><ul><li>The need for precise determination of ovulation time may lead to anxiety. </li></ul><ul><li>Cancellation rate % 6. In natural cycles, increased age decreases fecundity. </li></ul>
  42. 42. CONCLUSION- II <ul><li>Hormonal controlled cycle ; In cases with functioning ovary but who have anovulatory or irregular cycles, it is necessary for adequate endometrial preparation. </li></ul><ul><li>Therefore, as programmed E2 and P replacement can be performed with GnRH-a , it can be carried out without this program. </li></ul>
  43. 43. CONCLUSION- III <ul><li>While previously it was believed that with GnRH-a employment at the beginning, synchronization between embryo and endometrial development was simplified, the need for USG and endocrin monitorization decreased, </li></ul><ul><li>cancellation rate was reduced and transfer time could be controlled more easily. </li></ul>
  44. 44. CONCLUSION- IV <ul><li>At present; It has been established that endometrial preparation with exogenous E and P without using GnRH-a is simple, easy , effective and economical in frozen ET cases with active ovaries. </li></ul><ul><li>It is known that PR and IR in these cycles are the same with frozen ET cycles programmed with GnRH-a and naturel cycles. </li></ul>
  45. 45. CONCLUSION- V <ul><li>The type and administration route of the steroid form has no effect on the success of the frozen ET cycles. </li></ul>
  46. 46. CONCLUSION- VI <ul><li>Good quality of frozen – thawed embryos and the trilaminar sonographic pattern of endometrium may be reliable predictors of success in pregnancy. </li></ul>
  47. 47. CONCLUSION- VII <ul><li>Embryo quality evaluated morphologically was the most important clinical factor for succesful implantation of cryopreserved- thawed ET. </li></ul>
  48. 48. CONCLUSION- VIII <ul><li>Neither the mode of endometrium preparation nor the length of cryostorage appears to affect the outcome of frozen ET cycles. </li></ul>

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