Fet endometrial preparation

ENDOMETRIAL ENDOMETRIAL PREPARATION IN FROZEN PREPARATION IN FROZEN EMBRYO TRANSFER EMBRYO TRANSFER CYCLESCYCLES

Muammer DOGAN, Assoc. Prof. MDMuammer DOGAN, Assoc. Prof. MD

ENDOMETRIAL PREPARATION ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER IN FROZEN EMBRYO TRANSFER

CYCLESCYCLESNatural cycleNatural cycleHormon Controlled cycleHormon Controlled cycle→→ GnRH-a programmed with GnRH-a programmed with E2 and P administrationE2 and P administration→→Non GnRH-a programmed Non GnRH-a programmed with E2 and P administrationwith E2 and P administration

Natural Cycles in Frozen ETNatural Cycles in Frozen ET

Women with regular cyclesWomen with regular cyclesIn ovulatory cases, frozen ET is In ovulatory cases, frozen ET is successfully carried out after successfully carried out after spontaneous ovulation.spontaneous ovulation.Cohen 1988, Testart 1988, Muasher Cohen 1988, Testart 1988, Muasher 1991, Loh SKE 1999.1991, Loh SKE 1999.Is cheaper.Is cheaper.May be used in young cases. May be used in young cases. It is not the proper option when better It is not the proper option when better control and flexibility in timing is control and flexibility in timing is desireddesired..


It requires endogenous It requires endogenous hormone production.hormone production.Ovulation time must be Ovulation time must be identified clearly. This may identified clearly. This may cause anxiety. cause anxiety. Cancel rate 6% Cancel rate 6%

(Sathanandan 1991)(Sathanandan 1991)After 35 After 35 (Queenan 1995)(Queenan 1995) and and 40 40 (Al-Shawaf 1993), (Al-Shawaf 1993), fecundity fecundity with natural cycle is decreased with natural cycle is decreased in frozen ET. in frozen ET.


It can not be used in menstrual It can not be used in menstrual irregularity. irregularity. In many ART patients, In many ART patients, anovulation,irregular cyles,the presence anovulation,irregular cyles,the presence of PCOS and LPD prevents clear of PCOS and LPD prevents clear determination of ET time. For this determination of ET time. For this purpose, the use of CC and hMG is on the purpose, the use of CC and hMG is on the agenda. agenda.

Cohen;1988Cohen;1988The adverse effect of CC on endometrium, The adverse effect of CC on endometrium, potential side effects of hMG caused the potential side effects of hMG caused the transfer to the presently used protocols in transfer to the presently used protocols in all cases.all cases.


4 days before ovulation 4 days before ovulation monitorization in monitorization in ~~D8- D10D8- D10

(USG, E2, LH, P)(USG, E2, LH, P)DF › 14 mm LH measurementDF › 14 mm LH measurement2 days after ovulation ( DF loss 2 days after ovulation ( DF loss in USG, 2SD increase from the in USG, 2SD increase from the basal in P ) and 3 days after LH basal in P ) and 3 days after LH peak ET →peak ET →Progesteron support is not Progesteron support is not usually required. Sometimes Pusually required. Sometimes P may be given for luteal support.may be given for luteal support.

Frozen- thawed embryos Frozen- thawed embryos can be transferred to can be transferred to naturally cycling women naturally cycling women or to women who have or to women who have been primed with been primed with hormone replacement hormone replacement treatment with equal treatment with equal succes.succes.

Byrd W Semin Reprod Med Byrd W Semin Reprod Med 2002;20:372002;20:37..

Hormonally Manipulated Cycles Hormonally Manipulated Cycles in Frozen ETin Frozen ET

In cases whose ovary is In cases whose ovary is functional but who have functional but who have anovulatory and irregular anovulatory and irregular cyclescycles, frozen ET should be , frozen ET should be carried out only after carried out only after adequate endometrial adequate endometrial preparation.preparation.In these cases, ovulation may In these cases, ovulation may be induced by CC or hMG or ET be induced by CC or hMG or ET may be performed after may be performed after ovulation.ovulation.

Van der Auwera;1994.Van der Auwera;1994.


The fact that adequate The fact that adequate endometrial preparation endometrial preparation can be carried out with can be carried out with exogenous hormone exogenous hormone administration was administration was originially demonstrated originially demonstrated by Navot et al.by Navot et al. Navot;1989Navot;1989


It was shown that after It was shown that after GnRH-a down regulation, in GnRH-a down regulation, in cases with functional ovary, cases with functional ovary, exogenous steroids could exogenous steroids could enable adequate enable adequate endometrial preparation, endometrial preparation, simulating nonfunctional simulating nonfunctional ovary donation cycles.ovary donation cycles.

Muasher 1991, Younis 1996Muasher 1991, Younis 1996

Devroey 1998Devroey 1998


GnRH-a EmploymentGnRH-a EmploymentAdvantagesIt simplifies the synchronization between embryo and endometrial development. (E.g;anovulation and irregular cycle)It decreases the need for USG and endocrine monitorizationThe rate of cancellation decreases.Transfer time is more readily controlled.

Smitz 1992, Keltz 1995.


GnRH-a employmentGnRH-a employmentDisadvantages-Hypoestrogenic structure-Paradoxal development-Cyst formation

-The need for maintaining daily exogenous hormone replacement throughout first trimester in pregnancy -Prolongation of the duration of treatment. Smitz 1992, Keltz 1995.


GnR-a, is GnR-a, is necessarynecessary for sufficient for sufficient endometrial hormonal manipulation in endometrial hormonal manipulation in anovulatory frozen ET cases with anovulatory frozen ET cases with functional ovary.functional ovary.Meldrum DR 1989, Remohij 1995, Meldrum DR 1989, Remohij 1995, Younis JS 1996, El-Toukhy T;2004.Younis JS 1996, El-Toukhy T;2004.

The employment of GnRH-a for The employment of GnRH-a for controlled endometrial preparation in controlled endometrial preparation in recipients with functional ovaries in recipients with functional ovaries in frozen ET programs is frozen ET programs is not necessarynot necessary..de Ziegler D 1991, Pattison HA 1992, de Ziegler D 1991, Pattison HA 1992, Yen B 1995, Queenan JT 1997, Simon A Yen B 1995, Queenan JT 1997, Simon A 1998, Oborna I 2004.1998, Oborna I 2004.


E can be given,E can be given,

Orally, transdermally, Orally, transdermally, vaginally, s.cvaginally, s.c

P can be givenP can be givenOrally, IM, vaginally, nasally, Orally, IM, vaginally, nasally, rectally, sublinguallyrectally, sublinguallyThe best route of The best route of administration of E and P in administration of E and P in preparation for ET is unclearpreparation for ET is unclear..

In endometrial In endometrial preparation in Frozen ET preparation in Frozen ET cases, there is no cases, there is no difference between difference between sublingual Psublingual P (3x400mg) (3x400mg) and and parenteral Pparenteral P(P in oil 50mg/g) with (P in oil 50mg/g) with regard to IR.regard to IR.

Dale WS; 1996.Dale WS; 1996.

Vaginal P (%8 Crinone)Vaginal P (%8 Crinone) VV İ.M P (100 mg)İ.M P (100 mg)

Endometrial preparation was Endometrial preparation was determined to be enough in all cases. determined to be enough in all cases. Patient compliance is better with Patient compliance is better with vaginal use. vaginal use. (less feeling of pain and discomfort)(less feeling of pain and discomfort)There is no difference in the rate and There is no difference in the rate and maintainance of pregnancy.maintainance of pregnancy.

Gibbons W;1998.Gibbons W;1998.

In programmed frozen ET, In programmed frozen ET, combined oral E2 and combined oral E2 and vaginal P employment is an vaginal P employment is an effective, simple and effective, simple and inexpensive approach. There inexpensive approach. There is no stastistically significant is no stastistically significant difference between IM and difference between IM and vaginal route in terms of P vaginal route in terms of P yield.yield. Lightman A;1999.Lightman A;1999.

The Estraderm TTS The Estraderm TTS 100/Crinone 8% protocol 100/Crinone 8% protocol seems to be superior to seems to be superior to stimulation protocols and stimulation protocols and even to other protocols even to other protocols reported so far for artificial reported so far for artificial cycles with exogenous cycles with exogenous oestradiol and progesterone oestradiol and progesterone treatment.treatment.

Bals-Pratch; 1999.Bals-Pratch; 1999.

Hormonally Manipulated Cycles Hormonally Manipulated Cycles in Frozen ET in Frozen ET

( ( GnRH-a Programmed)GnRH-a Programmed)D2(Follicular) V D21(Luteal) D2(Follicular) V D21(Luteal) GnRH-a 10-14 days GnRH-a 10-14 days (Buserelin 500mcg, Nafarelin 2x2/g, (Buserelin 500mcg, Nafarelin 2x2/g, Triptorelin 3.75 mg or 0.1mg/g,LA Triptorelin 3.75 mg or 0.1mg/g,LA 0.5mg/d.)0.5mg/d.)If Down regulation If Down regulation (P‹ 0.5ng, E2 ‹50pg, LH ‹ 5 mIU)(P‹ 0.5ng, E2 ‹50pg, LH ‹ 5 mIU) did did not occur, treatment is maintained for not occur, treatment is maintained for one more week and values are one more week and values are repeatedrepeatedAfter down regulation, the duration of After down regulation, the duration of proliferative phase which will last until proliferative phase which will last until the commencement of progesteron is the commencement of progesteron is approximately 12-20 days.approximately 12-20 days.


( ( GnRH-a Programmed)GnRH-a Programmed)HRT is initiated after down regulation.D1-D8 E2 Valerat or micronized E2

2 mgD9-D11 4 mgD12 6 mgD14 USG End>8mm Luteal support Micronised P 2x400mg vaginal cap.Crinone 8% (90 mg) vaginal gel Cylogest 400 mg vag.tab 2X1


( ( GnRH-a Programmed)GnRH-a Programmed)D16-17D16-17 ET ET

(48-72 hours after P )(48-72 hours after P )

After ET 14 day After ET 14 day ββ-hCG-hCG If pregnancy is present E2 If pregnancy is present E2

8 mg and P at the same or 8 mg and P at the same or twofold dose is twofold dose is administered until administered until placental autonomyplacental autonomy..

Porcu E;1997.Porcu E;1997.


( ( GnRH-a Programmed)GnRH-a Programmed)Transdermal E2 Transdermal E2

(Estraderm TTS 100)(Estraderm TTS 100)(Patch should be changed every two (Patch should be changed every two

days)days)After Down regülasyon; (e.g.;LA After Down regülasyon; (e.g.;LA

0.5mg/g sc)0.5mg/g sc)D1-D8D1-D8 E TTS 0.1 mgE TTS 0.1 mgD9-D10D9-D10 E TTS 0.2 mgE TTS 0.2 mgD11-D12D11-D12 E TTS 0.3 mgE TTS 0.3 mgD13-D14D13-D14 E TTS 0.4 mgE TTS 0.4 mgD15 D15 → E TTS 0.2 mgLuteal support P İn oil 50mg IM. LA is discontinued.


( ( GnRH-a Programmed)GnRH-a Programmed)

D17 ETD17 ET After ET, 14th day After ET, 14th day ββ-hCG-hCG

If pregnancy is present, If pregnancy is present, E2 ve P dose E2 ve P dose administered until administered until placental autonomy.placental autonomy.

Muasher;1991


( ( GnRH-a Programmed)GnRH-a Programmed)D1 Mikronised 17βE2(Estrafem)

4mg/g 2x1D7 E2, P, USG measurement

E2<800pmol/L orEnd <8mm

Dose 6-8 mg/d is maintained for 5-10 more days

End≥8mm Luteal supportMikronised P 3x300mg Vag..

SSimon A;1998imon A;1998(First controlled randomized study(First controlled randomized study))


( ( GnRH-a Programmed)GnRH-a Programmed) 48-72 hours after P ET48-72 hours after P ET

After ET 14th day After ET 14th day ββ-hCG-hCGIf pregnancy is present, this If pregnancy is present, this dose is given until placental dose is given until placental autonomyautonomySSimon A;1998imon A;1998(First controlled randomized (First controlled randomized study)study)


( Non ( Non GnRH-a Programmed)GnRH-a Programmed)D1 Mikronised E2 Estrafem(6mg/d 3x1 p.o)D1 Mikronised E2 Estrafem(6mg/d 3x1 p.o)(In previous schemes 2mg/d (In previous schemes 2mg/d

Pattison;1992,Pattison;1992, Queenan;1997.)Queenan;1997.)(Today, E2 treatment is started on cyle day 25 of (Today, E2 treatment is started on cyle day 25 of the previous cycle)the previous cycle)

The aim of high dose E is supression of The aim of high dose E is supression of gonadotropic cells, follıculogenesis and the gonadotropic cells, follıculogenesis and the prevention of LH peak.)prevention of LH peak.)D7 E2, End. thickness (EndD7 E2, End. thickness (End≥8mm)

Luteal support (Mic.P 3x300mg vaginal) (D7 – Luteal sup.(D7 – Luteal sup. PP≥6nmol/L VV D20 End. thickness D20 End. thickness <<8 mm cycle cancellation)8 mm cycle cancellation)

Simon A;1999.Simon A;1999.


( Non ( Non GnRH-a Programmed)GnRH-a Programmed)48-72 hours after P ET→48-72 hours after P ET→

14th day after ET →14th day after ET → ββ-hCG-hCGIf pregnancy is present, this dose is If pregnancy is present, this dose is given until placental autonomy.given until placental autonomy.The rate of cancellation is low, The rate of cancellation is low, The probability of premature P The probability of premature P secretion is small.secretion is small.Conclusion : 6mg/d Mic. E2, Conclusion : 6mg/d Mic. E2, gonadotropin secretion is sufficient gonadotropin secretion is sufficient for prevention of spontaneous for prevention of spontaneous ovulation and endometrial ovulation and endometrial preparation.preparation.


Hormonally Manipulated Cycles Hormonally Manipulated Cycles in Frozen ET in Frozen ET ( Non ( Non GnRH-a Programmed)GnRH-a Programmed)

Serum E2 level is Serum E2 level is unimportant in decision unimportant in decision for ET. Only one serum P for ET. Only one serum P level measured with USG level measured with USG when starting P is enough when starting P is enough for decision. for decision. If endometrial thickness If endometrial thickness is adequate and is adequate and premature P secretion is premature P secretion is absent, P support may absent, P support may continue after ET. continue after ET.



( Non ( Non GnRH-a Programmed)GnRH-a Programmed)

D1D1 4mg/g E2 Valerate4mg/g E2 ValerateD14D14 P measurement (for P measurement (for spontaneous ovulation)spontaneous ovulation)(p›0.9 ng/ml cycle cancellation)(p›0.9 ng/ml cycle cancellation)D15D15 Mic.P Mic.P 300mg/g vaginal300mg/g vaginalD19 D19 ETETD29D29 ββ-hCG-hCGIf pregnancy is present, E2 and P If pregnancy is present, E2 and P dose x2 is maintained until dose x2 is maintained until placental autonomy.placental autonomy.

Lelaider C; 1995.Lelaider C; 1995.


( Non ( Non GnRH-a Programmed)GnRH-a Programmed)The high PR observed The high PR observed after transferring after transferring blastoctsts on the 5th day blastoctsts on the 5th day of endometrial exposure of endometrial exposure to P in controlled E2 and to P in controlled E2 and P replacement cycles.P replacement cycles.

Lelaider C; 1995.Lelaider C; 1995.

Hormonally Manipulated Cycles in Hormonally Manipulated Cycles in Frozen ET Frozen ET

( Non ( Non GnRH-a Programmed)GnRH-a Programmed)Endometrial preparation with Endometrial preparation with exogenous E and P without exogenous E and P without GnRH-a is simple, easy and GnRH-a is simple, easy and efficient in frozen ET cases efficient in frozen ET cases with active ovary.with active ovary.

Jaroudi;1991,Jaroudi;1991,Pattison HA;1992, Pattison HA;1992, Lelaider C; 1995, Lelaider C; 1995, Queenan JT;1997, Queenan JT;1997, Simon A; 1999,Simon A; 1999,Dal Prato L;2002,Dal Prato L;2002,

It seems to be appropriate to It seems to be appropriate to start progesterone start progesterone administration before transfer in administration before transfer in oocyte donation programmes as oocyte donation programmes as well as transfer of cryopreserved well as transfer of cryopreserved / thawed cell as soon as the / thawed cell as soon as the endometrium is developed endometrium is developed sufficiently (8mm,trilaminar sufficiently (8mm,trilaminar pattern), and to perform the pattern), and to perform the embryo transfer not before day 3 embryo transfer not before day 3 - 4 of progesterone treatment, - 4 of progesterone treatment, i.e. embryo development on day i.e. embryo development on day 2-3.2-3. Nawroth F;2005.Nawroth F;2005.

Retrospective AnalysisRetrospective Analysis

A.A. LA LA ++ Transdermal E2 Transdermal E2 patchpatchB.B. LA LA ++ Oral Mic. E2 Oral Mic. E2C.C. Oral Mic. E2 Oral Mic. E2Down regulation with Down regulation with GnRH-a is not necessary. GnRH-a is not necessary. Regimes not programmed Regimes not programmed with GnRH- are simple and with GnRH- are simple and more economical. more economical. Yee;1995.Yee;1995.

A.A. Naturel cycle Naturel cycle (Luteal P support)(Luteal P support)B.B. Artificial preparation Artificial preparation (GnRH-a (GnRH-a ++ E2 E2 ++ P) P)C.C. Ovarian Stimulation Ovarian Stimulation (GnRH-a (GnRH-a ++ hMG hMG ++ hCG hCG ++ P) P)

Thre is no significant Thre is no significant difference in terms of IRdifference in terms of IR..

Vasilios T;1996, Tanos V; 1996.Vasilios T;1996, Tanos V; 1996.

A-A- 400 mcg buserelin acetate 400 mcg buserelin acetate + 6 mg E2 valerate + + 6 mg E2 valerate +

(800 mg/d P)(800 mg/d P)B-B- 6 mg E2 valerate 6 mg E2 valerate

(800 mg/d P)(800 mg/d P)Medicated frozen embryo Medicated frozen embryo replacement cycles timed by replacement cycles timed by endometrial thickness endometrial thickness measurement alone without measurement alone without monitoring or suppression of monitoring or suppression of ovarian activity are associated ovarian activity are associated with reduced outcome.with reduced outcome.

El-Toukhy T;2004.El-Toukhy T;2004.

InIn Frozen Frozen EmbryoTransfer;EmbryoTransfer;

Significant effect -Significant effect -Patient Patient ageage, number of embryos , number of embryos replacedreplacedNo significant effect -No significant effect -Duration of storage of embryosDuration of storage of embryosStimulation typeStimulation typeCause of infertilityCause of infertility

((Avery and Brinsden;1997)Avery and Brinsden;1997)

Embryo Embryo quality evaluated quality evaluated morphologically was the morphologically was the most important clinical most important clinical factor for succesful factor for succesful implantation of implantation of cryopreserved- thawed ET.cryopreserved- thawed ET.

Kondo I;1996.Kondo I;1996.

Good quality of frozen Good quality of frozen thawed embryos and thawed embryos and the trilaminar the trilaminar sonographic pattern of sonographic pattern of endometrium may be endometrium may be reliable predictors of reliable predictors of success in pregnancy.success in pregnancy. Zhu Zhu Y;2001Y;2001..

For thin For thin endometria,endometria,there was not a there was not a observed trend observed trend suggesting lower suggesting lower PRs.PRs.

Jerome HC;2004.Jerome HC;2004.

Neither the mode of Neither the mode of endometrium preparation nor endometrium preparation nor the length of cryostorage the length of cryostorage appears to affect the outcome appears to affect the outcome of frozen ET cycles.of frozen ET cycles.

Kolibianakis EM;2003.Kolibianakis EM;2003.

The type and administration The type and administration route of the steroid form has route of the steroid form has no effect on the success of the no effect on the success of the frozen ET cycles.frozen ET cycles.

CONCLUSION- ICONCLUSION- I

Endometrial preparation is cheaper with Endometrial preparation is cheaper with natural cycles. natural cycles. It can not be used in menstrual irregularity. It can not be used in menstrual irregularity. Therefore, it should be preferred in younger Therefore, it should be preferred in younger cases.cases.It is not a suitable choice when better control It is not a suitable choice when better control and fleixbility in timing is desired. and fleixbility in timing is desired. The need for precise determination of The need for precise determination of ovulation time may lead to anxiety. ovulation time may lead to anxiety. Cancellation rate % 6. In natural cycles, Cancellation rate % 6. In natural cycles, increased age decreases fecundity.increased age decreases fecundity.

CONCLUSION- IICONCLUSION- II

Hormonal controlled cycle ;Hormonal controlled cycle ; In cases In cases with functioning ovary but who have with functioning ovary but who have anovulatory or irregular cycles, it is anovulatory or irregular cycles, it is necessary for adequate endometrial necessary for adequate endometrial preparation.preparation.

Therefore, as programmed E2 and P Therefore, as programmed E2 and P replacement can be performed with replacement can be performed with GnRH-a , it can be carried out without GnRH-a , it can be carried out without this program.this program.

CONCLUSION- IIICONCLUSION- III

While previouslyWhile previously it was believed that it was believed that with GnRH-a employment at the with GnRH-a employment at the beginning, synchronization between beginning, synchronization between embryo and endometrial development embryo and endometrial development was simplified, the need for USG and was simplified, the need for USG and endocrin monitorization decreased, endocrin monitorization decreased, cancellation rate was reduced and cancellation rate was reduced and transfer time could be controlled more transfer time could be controlled more easily.easily.

CONCLUSION- IVCONCLUSION- IV

At present; At present; It has been established It has been established that endometrial preparation with that endometrial preparation with exogenous E and P without using exogenous E and P without using GnRH-a is simple, easy , effective and GnRH-a is simple, easy , effective and economical in frozen ET cases with economical in frozen ET cases with active ovaries.active ovaries.It is known that PR and IR in these It is known that PR and IR in these cycles are the same with frozen ET cycles are the same with frozen ET cycles programmed with GnRH-a and cycles programmed with GnRH-a and naturel cycles.naturel cycles.

CONCLUSION- VCONCLUSION- V

The type and The type and administration route of administration route of the steroid form has no the steroid form has no effect on the success of effect on the success of the frozen ET cycles.the frozen ET cycles.

CONCLUSION- VICONCLUSION- VI

Good quality of frozen – Good quality of frozen – thawed embryos and the thawed embryos and the trilaminar sonographic trilaminar sonographic pattern of endometrium pattern of endometrium may be reliable predictors of may be reliable predictors of success in pregnancy. success in pregnancy.

CONCLUSION- VIICONCLUSION- VII

Embryo Embryo quality evaluated quality evaluated morphologically was the morphologically was the most important clinical most important clinical factor for succesful factor for succesful implantation of implantation of cryopreserved- thawed ET.cryopreserved- thawed ET.

CONCLUSION- VIIICONCLUSION- VIII

Neither the mode of Neither the mode of endometrium preparation endometrium preparation nor the length of nor the length of cryostorage appears to cryostorage appears to affect the outcome of frozen affect the outcome of frozen ET cycles.ET cycles.

Fet endometrial preparation

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