Frozen embryo transfer cycles By Dr . Ghada Harfoush

1. Optimal Endometrial Preparation for
Frozen Embryo Transfer Cycles
By
GHADA HARFOUSH
Consultant of Obstetric&Gynecology
Integrated Fertility Center

2. • With significant improvements in
cryopreservation technology
(virtification) the number of frozen
ET IVF cycles is increasing and
may surpass in numbers and
success rates those of fresh cycles

3. Factors affecting the success rate of FET
cycles:
• Quality of the frozen embryo.
• The stage of the embryo at freezing.
• The survival rate after thawing.
• The number of embryo transferred.
• Storage duration&the technique of the
operator.

4. Optimal Endometrium Preparation for
FET cycles demands:
1- Different endometrial preparation
protocols.
2- Progesterone Support
3- Identification of receptive window of
implantation for ET.
These are of atmost importance for insuring the best

5. Endomertium Lining in IVF

6. Endometrial Preparation Protocols
1-Natural Cycles
True / Modified
2-Programmed (Artificial) Cycles
E and P
GnRHa, E and P
3-Ovulation induction
CC,Nolvadex,Letrozole or HMG
or a combination.

7. A.True Natural Cycle
• Need regular cycles and proven
ovulation
• Involves frequent monitoring of urine
and/or blood LH levels ,early luteal P
levels,and U/S monitoring of the
developing dominant follicle.
• For optimal FET results precise
idetification of the LH surge.

8. Method
• 1- D10-12 <3-5 days prior to estimated
ovulation day>
• Serial US: E thickness,follicular
development and to time the
commencement of testing for LH.
• LH (urine or blood) for detecting of
the LH surge.
• Progesterone levels.
2-US for evidence of ovulation

9. Method (cont)
• 3-FET
* 3-5 days after ovulation depending
on the stage of embryo when frozen.
* The day of ovulation corresponds to
the day of egg retrieval.
* If the embryo were frozen at day 3:
ovulation day + 3 is the right time to
transfer.
4-LPS with Progesterone

10. • Advantages
• Preferable to many women.
• No medication are used.
• Endocrine preparation of the
endometrium is achieved by
endogenous sex steroid production
from a developing follicle
• Disadvantages
• Identification of LH surge is difficult.
• Ovulation may not always occur even
in regular menstrual cycle.

11. B.Modified Natural Cycle
• To overcome the disadvantages of LH
monitoring “ Administering HCG to
initiate luteinization”
• Involve U/S monitoring of the
developing follicle, measurments of the
endometrial strips, and monitoring of
serum hormonal levels followed by
5000 IU of HCG when the dominant
follicle is >17mm and P level is low.

12. • Avantages:
Less U/S evalution due to the HCG
administration compared
with true NC-FET
• Disadvantages:
• Unexpected ovulation
• Difficult in ensuring timely ET.

13. Programmed (Artificial) Cycles
• Involve suppression of natural menstrual
cycle with or without the use of GnRH
agonist.
• This require exogenous E for the
proliferation of the endometrium,while
suppressing the developing dominant
follicle.
• In addition to P replacement to achieve
adequate secretory changes in the
endometrium .

14. Programmed FET Cycles
• Method:
• Estrogen administration on D2 or 3 of cycle by
either incremental or fixed levels [3 tab] until the
endometrial thickness on U/S has reached
approximately 8mm and then add progesterone
[400mg twice daily] for the numbers of days
proportional to the stage of development of the
embryo being transferred.
Paulson RJ.Fertil Steril 2011
•

15. • Method [Cont.]
ET
• If you are freezing on D3 Morula:
transfer on day 4 of progesterone.
• If freezing on D5 Blastocyst: transfer
on day 6 of progesterone.
LPS
• Estrogen and progesterone.

16. • Using GnRHa in Programmed
Cycles is to suppress temporarily
ovarian function,thus ensure the
prevention of luteinization that may
occurs when using E&P alone
(about 5%)

17. Programmed FET Cycles
It is the most convenient with respect to
limited monitoring requirements and
ease and flexibility of scheduling..
It is the best method for patient with
irregular cycles.
However, they have not been shown to
be superior to properly timed natural or
modified natural FET cycles..

18. Ovulation Induction
• In patient with anovulatory and
irregular cycles Letrozle is the 1st
choice for endometrial preparation for
FET.
• Dose of 2.5-5mg from D3 to D7 and
administration of HCG when the
follicles reach the criteria of maturity.
• ET after 4-5 days for embryos frozen at
72hr and after 6-7 days for the
blastocyst embryo.

19. Progesterone Supplementation
In FET cycles
• It has been well documented in elegant
pharmacological studies that
absorption of Progesterone into the
endometrium is superior with the
vaginal P compared with IM P
administration,whereas higher serum P
levels are measured after the injections
Bulletti C,Flamigni C.Hum Reprod 1997

20. • Traditionally higher serum P levels
were presumed to be better for the
FET outcomes.

21. • However,two recent retrospective
studies showed that increasing IM
P doses to achieve higher serum
levels does not translate into
improved outcomes
Brady PC,Kaser DJ,Assist Reprod Genetic 2014

22. • Also noted that high P levels
(>20ng/ml) on the day of transfer of
single euploid blastocysts were
associated with lower ongoing PRs
and lower live birth rates
Kofinas JD,Blakemore J.Assisst Reprod Genet 2015

23. • Natural FET cycles benefit from
vaginal P supplementation starting
after ET.
• Modified Natural FETcycles
P support after ET could be
optional and should use the most
convenient and cost effective P
preparation.

24. • Programmed cycles:
• The optimal form of Progesterone
supplementation has not been
established.
• Patients preference and
convenience, as well as costs
should be considered when
choosing either vaginal or IM P
preparations.

25. Window of IMPLANTATION:
Potential for Personalized ET
• For a human pregnancy to occur,a
normal embryo must implant in the
endometrium and for this to happen the
endometrium must be in a receptive
state.

26. • Most recently ,
microarray molecular analysis
(endometrial receptivity assay) for
hundreds of gene expression
alterations have been used to
demarcate the window of
implantation.
Ruiz-Alonso M,Blesa D.Fert Steril 2013

27. Simon et el.using microarray
molecular analysis in FET cycles
found that about 25% of the
endometrial biopsies were delayed
in relation to day 20( sixth day of P
adminstration).
Fertil Steril 2013

28. • Similarly,using simple endometrial
dating of endometrial biopsies
(Noyes criteria) also showed that
about 25% of samples were
delayed.
Gomaa H,Casper RF.Reprod Biomed Online 2015

29. • So the concept of personalized
FET by adding 1-3 days of P and
delaying FET in women with
demonstrated delayed endometrial
development.

30. • Another consideration,even if
timing of the window of
implantation is correct,is the
uterine activity at time of ET,either
spontaneous or resulting from
traumatic or difficult ET.

31. • It is known that E increases uterine
contractility and subendometrial
wave activity and that P
antagonizes this action to quiet the
uterus and reduce endometrial
waves.

32. • In controlled ovarian stimulation
for ART, supraphysiologic levels of
E are associated with multiple
subendometrial contraction
manifested as frequent
endometrial waves .

33. • Frequent endometrial waves in
the luteal phase are associated
with a lower PR as first
demonstrated by Fanchin and
colleagues in France.

34. • So augmentation with
Progesterone administration
when the contraction frequency
is high should result in
improved results.

35. Results of FET
In Integrated Fertility Center
• 2011 14.7 %
• 2012 27.4 %
• 2013 54.7 %
• 2014 37.0 %
• 2015 49.6 %
• 2016 50.0 %

36. Take Home Message
 Programmed FET cycles are the
most convenient,however the
optimal form of P supplementation
has not been established.

37. Take Home Message
• The window of implantation in
hormonally prepared cycles for FET
may be delayed in about one of four
women.
• In that cases adding 1-3 days of P and
delaying FET according to the
endometrial delay (personalized ET)
may lead to improved PRs.

38. Take Home Message
• In women having excessive wave
activity,administration of P could
improve PRs.

39. Thank you