ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES

ENDOMETRIAL ENDOMETRIAL PREPARATION IN PREPARATION IN FROZEN EMBRYO FROZEN EMBRYO TRANSFER CYCLESTRANSFER CYCLES

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 GnRH-a programmed with E2 and P with E2 and P administrationadministration→→Non GnRH-a Non GnRH-a programmed with E2 and programmed with E2 and P administrationP administration

Natural Cycles in Frozen Natural Cycles in Frozen ETET

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, Cohen 1988, Testart 1988, Muasher 1991, Loh SKE 1999.Muasher 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 It is not the proper option when better control and flexibility in better control and flexibility in timing is desiredtiming is desired..


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 (Sathanandan 1991)1991)After 35 After 35 (Queenan 1995)(Queenan 1995) and and 40 40 (Al-Shawaf 1993), (Al-Shawaf 1993), fecundity with natural cycle fecundity with natural cycle is decreased in frozen ET. is decreased 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 anovulation,irregular cyles,the presence of PCOS and LPD prevents presence of PCOS and LPD prevents clear determination of ET time. For clear determination of ET time. For this purpose, the use of CC and hMG this purpose, the use of CC and hMG is on the agenda. is on the agenda. Cohen;1988Cohen;1988The adverse effect of CC on The adverse effect of CC on endometrium, potential side effects endometrium, potential side effects of hMG caused the transfer to the of hMG caused the transfer to the presently used protocols in all cases.presently used protocols in 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 2 days after ovulation ( DF loss in USG, 2SD increase loss in USG, 2SD increase from the basal in P ) and 3 from the basal in P ) and 3 days after LH peak → ET days after LH peak → ET Progesteron support is not Progesteron support is not usually required. Sometimes usually required. Sometimes PP may be given for luteal may be given for luteal support.support.

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

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

Hormonally Manipulated Hormonally Manipulated Cycles in Frozen ETCycles in 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 In these cases, ovulation may be induced by CC or may be induced by CC or hMG or ET may be hMG or ET may be performed after ovulation.performed after ovulation.

Van der Van der Auwera;1994.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, GnRH-a down regulation, in cases with functional in cases with functional ovary, exogenous steroids ovary, exogenous steroids could enable adequate could enable adequate endometrial preparation, endometrial preparation, simulating nonfunctional simulating nonfunctional ovary donation cycles.ovary donation cycles.

Muasher 1991, Younis Muasher 1991, Younis 19961996

Devroey Devroey 19981998


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 endometrial hormonal manipulation in anovulatory frozen ET cases with in 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 controlled endometrial preparation in recipients with functional ovaries in recipients with functional ovaries in frozen ET programs is in frozen ET programs is not not necessarynecessary..de Ziegler D 1991, Pattison HA de Ziegler D 1991, Pattison HA 1992, Yen B 1995, Queenan JT 1997, 1992, Yen B 1995, Queenan JT 1997, Simon A 1998, Oborna I 2004.Simon A 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 given

Orally, IM, vaginally, Orally, IM, vaginally, nasally, rectally, nasally, rectally, sublinguallysublingually

The best route of The best route of administration of E and P in administration of E and P in preparation for ET is preparation for ET is unclearunclear..

In endometrial In endometrial preparation in Frozen preparation in Frozen ET cases, there is no ET 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 determined to be enough in all cases. cases. Patient compliance is better with Patient compliance is better with vaginal use. vaginal use. (less feeling of pain and (less feeling of pain and discomfort)discomfort)There is no difference in the rate There is no difference in the rate and maintainance of pregnancy.and 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 reported so far for artificial cycles with artificial cycles with exogenous oestradiol and exogenous oestradiol and progesterone treatment.progesterone treatment.

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

Hormonally Manipulated Hormonally Manipulated Cycles in Frozen ET Cycles 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 (Buserelin 500mcg, Nafarelin 2x2/g, Triptorelin 3.75 mg or 2x2/g, Triptorelin 3.75 mg or 0.1mg/g,LA 0.5mg/d.)0.1mg/g,LA 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 not occur, treatment is did not occur, treatment is maintained for one more week maintained for one more week and values are repeatedand values are repeatedAfter down regulation, the After down regulation, the duration of proliferative phase duration of proliferative phase which will last until the which will last until the commencement of progesteron is 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 If pregnancy is present E2 8 mg and P at the E2 8 mg and P at the same or twofold dose is same or 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 (Patch should be changed every two 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--

hCGhCGIf pregnancy is If pregnancy is present, E2 ve P dose present, 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 support

Mikronised 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-hCG

If pregnancy is present, If pregnancy is present, this dose is given until this dose is given until placental autonomyplacental autonomy

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


( Non ( Non GnRH-a GnRH-a Programmed)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 (Today, E2 treatment is started on cyle day 25 of the previous cycle)of 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 GnRH-a Programmed)Programmed)48-72 hours after P → ET48-72 hours after P → ET

14th day after ET→ 14th day after ET→ ββ-hCG-hCGIf pregnancy is present, this dose If pregnancy is present, this dose is given until placental autonomy.is 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 gonadotropin secretion is sufficient for prevention of sufficient for prevention of spontaneous ovulation and spontaneous ovulation and endometrial preparation.endometrial preparation.

Simon A;1999.Simon A;1999.

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

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

Simon Simon A;1999.A;1999.


( Non ( Non GnRH-a GnRH-a Programmed)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 (p›0.9 ng/ml cycle cancellation)cancellation)D15D15 Mic.P Mic.P 300mg/g vaginal300mg/g vaginalD19 D19 ETETD29D29 ββ-hCG-hCGIf pregnancy is present, E2 If pregnancy is present, E2 and P dose x2 is maintained and P dose x2 is maintained until placental autonomy.until placental autonomy.

Lelaider C; 1995.Lelaider C; 1995.

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

Lelaider C; 1995.Lelaider C; 1995.

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

( Non ( Non GnRH-a Programmed)GnRH-a Programmed)Endometrial preparation Endometrial preparation with exogenous E and P with exogenous E and P without GnRH-a is simple, without GnRH-a is simple, easy and efficient in easy and efficient in frozen ET cases with frozen ET cases with active ovary.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 administration before transfer in oocyte donation in oocyte donation programmes as well as programmes as well as transfer of cryopreserved / 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 embryo transfer not before day 3 - 4 of progesterone day 3 - 4 of progesterone treatment, i.e. embryo treatment, i.e. embryo development on day 2-3.development on day 2-3.

Nawroth F;2005.Nawroth F;2005.

Retrospective AnalysisRetrospective Analysis

A.A. LA LA ++ Transdermal E2 patch Transdermal E2 patch

B.B. LA LA ++ Oral Mic. E2 Oral Mic. E2

C.C. Oral Mic. E2 Oral Mic. E2

Down regulation with GnRH-a Down regulation with GnRH-a is not necessary. Regimes is not necessary. Regimes not programmed with GnRH- not programmed with GnRH- are simple and more are simple and more economical. 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; Vasilios T;1996, Tanos V; 1996.1996.

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 ovarian activity are associated with reduced associated with reduced outcome.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 Avery and Brinsden;1997)Brinsden;1997)

Embryo Embryo quality quality evaluated morphologically evaluated morphologically was the most important was the most important clinical factor for succesful clinical 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 Y;2001Zhu Y;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 endometrium preparation nor the length of cryostorage nor the length of cryostorage appears to affect the appears to affect the outcome of frozen ET cycles.outcome 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 no effect on the success of the frozen ET cycles.the 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 It can not be used in menstrual irregularity. irregularity. Therefore, it should be preferred in Therefore, it should be preferred in younger cases.younger cases.It is not a suitable choice when better It is not a suitable choice when better control and fleixbility in timing is desired. control 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 In cases with functioning ovary but cases with functioning ovary but who have anovulatory or irregular who have anovulatory or irregular cycles, it is necessary for adequate cycles, it is necessary for adequate endometrial preparation.endometrial preparation.

Therefore, as programmed E2 and Therefore, as programmed E2 and P replacement can be performed P replacement can be performed with GnRH-a , it can be carried out with GnRH-a , it can be carried out without this program.without 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 GnRH-a is simple, easy , effective and economical in frozen ET cases and economical in frozen ET cases with active ovaries.with 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 administration route of the steroid form of the steroid form has no effect on the has no effect on the success of the frozen success of the frozen ET cycles.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 may be reliable predictors of success in pregnancy. of 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 affect the outcome of frozen ET cycles.frozen ET cycles.

ENDOMETRIAL PREPARATION IN FROZEN EMBRYO TRANSFER CYCLES

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