Endometrial preparation for Thawed Embryo Replacement

Implantation

Interaction between an embryo and the endometrium

This process seems to be affected by two crucial factors ;

Endometrial receptivity

Synchronization between the embryo developmental stage and endometrial profile during the window of implantation

Endometrial receptivity needs

2 hormons;
Estrogen and progesterone

An important factor in the process of embryo implantation is endometrial receptivity and synchronisation between embryonic and endometrial development.

Keypoints in performing FET

Selecting proper embryos used for FET
Accurate synchronization of endometrium and embryos
Sufficient luteal support

Endometrial preperation & FET

Timing of embryo transfer is determined by detecting the spontaneous LH surge or by administering hCG to initiate luteinization
A frequently employed alternative approach is represented by ‘artificial cycle protocols’ in which exogenous estrogens and progesterones are administered, with or without co-treatment with GnRH agonists

Protocols for endometrial preperation

Naturel cycle
Naturel cyle + hCG (Modified NC)
Ovulation induction (CC, Letrozol, Gnd) + hCG
Artificial cycle FET (AC-FET)
- –GnRh-a programmed with E2 and P administration
- –Non GnRh-a programmed with E2 and P administration

Naturel Cycle in FET

Women with regular cycles (Ovulatory cases)
Cheaper
May be used in young cases
It is not proper option when better control and flexibility in timing is desired
It requires endogeneous hormon production
Ovulation time must be identified clearly
This may cause anxiety, Cancel rate %6

Naturel Cycle in FET

It can not be used in;
Menstrual irregularity
PCOS, anovulation, LPD prevents clear determination of ET time
CC, Letrozol and Gnd can be used for timing of ovulation and ET

Naturel Cycle & technique

4 days before ovulation, monitorization starts D 8-9
DF > 14 mm LH measurement
Progestereron support is not usually required, sometimes P may be given for luteal support

Naturel Cycle & technique

In order to assess the LH levels correctly, determination should be performed at least daily, and preferably twice a day.
LH urine kits have a large variation in thresholds, which involve the risk of up to 30% of false-negative testing, and are often reported by patients as being difficult to interpret

Miller and Soules, 1996; Guermandi et al., 2001; O’Connor et al., 2006

modified NC-FET

To overcome the disadvantages of LH monitoring, hCG triggering of ovulation is often employed in NC-FET in what is termed ‘modified NC-FET’.
This approach does not require LH monitoring but regular ultrasound evaluation of the dominant follicle is required to ensure appropriate timing of hCG administration.
As soon as the dominant follicle is of sufficient size (17–18 mm) hCG is administered as a surrogate to the endogenous LH surge to trigger final oocyte maturation and ovulation, which takes place 36–38 h later

Andersen et al., 1995

Artificial cycle FET (AC-FET)

Estrogen and progesterone are administered in a sequential regimen which aims to mimick the endocrine exposure of the endometrium in the normal cycle.
Initially, estradiol is given in order to cause proliferation of the endometrium, while suppressing the development of the dominant follicle.
This is continued until the endometrium is observed to be 7–9 mm thick on ultrasound, at which time progesterone is added to initiate secretory changes

El-Toukhy et al.,2008

Artificial cycle FET (AC-FET)

The physiological mid-cycle shift from estrogen to progesterone is thus emulated

Dor et al., 1991; Jaroudi et al., 1991

The timing of embryo thawing and transfer is planned according to the moment of progesterone supplementation
The administration of estrogen and progesterone does not guarantee complete pituitary suppression, and a dominant follicle may therefore occur.
Should the follicle undergo spontaneous luteinization then the endometrium may be exposed to progesterone earlier, risking incorrect timing of thawing and transferring

Endometrial thickness and fet outcome

Endometrial thickness

of 9–14 mm before P supplementation is associated with

a higher chance of implantation and pregnancy compared

with a thickness of 7–8 mm

HRT for FET

E can be given;
Orally, transdermally, vaginally, sc
P can be given;
Orally, IM, vaginally, nasally, rectally, subligually, rectally
The best route of administration of E and P in preperation for ET is unclear

Combined oral E2 and vaginal P

Effective
Simple
İnexpensive
Theree is no statistically significant difference between IM and vaginal route of P

HRT in FET (Gn RH-a Programmed)

HRT is initiated after down regulation
D1-D8 E2 Valerat or micronized E2 2 mg
D9-11 4 mg
D – 12 6 mg
D 14 USG > 8 mm luteal support
Micronised P 2 * 400 mg vaginal cap.
Crinone % 8 (90 mg) vaginal gel
Cliogest 400 mg vag. tab. 2 * 1

GnRH-a Employment Advantages

Synchronization between embryo and endometrial development

(anovulation and irregular cycle)

Decreases the need for USG and hormonal monitorization
Decreases cancellation rate
Controlled ET time

GnRH-a Employment Disadvantages

Prolongation of duration of treatment
Hypoestrogenic structure
Flare effect, cyst formation
GnRH-a for controlled endometrial preperation in FET recipients is not necessary

de Zeigler D 1991, Queenan JT 1997, Simon A 1998, Oborna I 2004

In FET

Significant effect

Age, number of embryos transferred, embryo quality, endometrial pattern and thickness

No significant effect

Stimulation type
Cause of infertility
Duration of storage

Kondo I, 1996, Avery 1997, Zhu Y, 2001, Kolibianakis EM Jerome HC, 2004

Despite the growing importance of FET in the treatment of subfertility there is little consensus on the best method for endometrium preparation in ovulatory women

Ghobara and Vandekerckhove, 2008;Weissman et al., 2009

Recent Cochrane review analysing a number of different protocols used prior to FET, concluded that there is currently no evidence to support the superiority of any one protocol over the other.

Ghobara and Vandekerckhove, 2010

E+P HRT vs Naturale cycle / Klinik gebelik

Cochrane 2010

True NC versus modified NC: pooled result of all studies

NC versus AC

NC versus AC with GnRH agonist

AC versus AC with GnRH agonist

Cycle cancellation

NC-FET poses the risk of unobserved ovulation. If ovulation occurs without notice, accurate planning of embryo thawing and transfer is not possible, which results in cycle cancellation (7–12%)

Fatemi et al., 2010; Hill et al., 2010

AC-FET does not guarantee complete down-regulation, luteinization may occur in 5% of the cases

El Toukhy et al., 2004

This meta-analysis revealed no significant advantage of one specific approach to prepare the endometrium for FET in terms of clinical pregnancy rates or live birth rates.

RESULT

CONCLUSION

Naturel cycle FET and HRT priming FET have equal success
Endometrial preperation with exogeneous E and P without using GnRH-a is simple,easy, effective and economical in FET cases
The type and administration route of the steroid form has no effect on the success of the FET cycles
For decreasing abortion rate in FET cycles;
vaginal progesterone gel dose administration 180 mg recommended, (2 * 90) morning and late afternoon
Minimum 12 days Estrogen intake before P
Blastosist ET at on Day six of P treatment
Doubling of the progesterone dose in patients receiving endometrial priming with oestradiol and progesterone prior to FET increased the clinical pregnancy rate per transfer and significantly reduced the biochemical pregnancy rate

Orvieto et al. 2007 , Check et al. 2010

that the viability of an early pregnancy is dependent on a certain threshold of progesterone.
The unanswered question regards how high the progesterone concentration should be. Interestingly, the concentration does not seem to be constant in all women as visualized in earlier studies, which showed significant histological endometrial differences in patients treated according to the same protocol

Sudoma et al.,2011

Endometrial preparation for Thawed Embryo Replacement