Endometrial Preparation in Frozen Embryo Transfer Cycles

Study Overview
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Brief Summary
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In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. Endometrial preparation is done by either natural, artificial (Hormonal replacement therapy HRT) , modified natural methods or mild ovarian stimulation. HRT cycle has a better schedualization however, there are some reports about higher rates of miscarriage, pregnancy induced hypertension (PIH) and preeclampsia (PET) in HRT cycles. A recent study has found that incorporation of the aromatase inhibitor (letrozole) to HRT cycles was associated with better FET outcomes in comparison to hormonal replacement therapy cycles alone. Meanwhile, mild ovarian stimulation protocol can be done either by oral drugs like letrozole or by letrozole plus gonadotropins . So this study aims to compare the reproductive outcomes in two endometrial preparation protocols for frozen embryo transfer cycles; letrozole mild ovarian stimulation versus HRT plus letrozole incorporation.

Detailed Description
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In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. This can be done by hormonal replacement therapy (HRT), natural cycles (NC), modified natural cycles or mild ovarian stimulation. In hormonal replacement therapy cycle, estrogen and progesterone are sequentially given to resemble the hormonal course of the natural cycle . Hormonal replacement therapy cycle has a better schedualization and is used for patients with irregular cycles as polycystic ovary syndrome ( PCOS). However, there are some reports about higher rates of miscarriage, pregnancy induced hypertension (PIH) and preeclampsia (PET) in HRT cycles. A recent study has found that incorporation of the aromatase inhibitor (letrozole) to HRT cycles was associated with better FET outcomes in comparison to HRT cycles alone. Ongoing pregnancy rate (OPR) was higher in HRT plus letrozole group than HRT only group. Letrozole is a third-generation aromatase inhibitor that leads to mono-ovulatory cycles with short half-life . Miller and his colleagues found that letrozole increased Integrin expression and improved pregnancy and implantation rates among women with endometrial receptivity defects . Another study found that ovarian stimulation with letrozole was associated with increase in the expression of uterine receptivity markers including integrin, leukemia inhibitory factor, and L-selectin.

Official Title
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Hormonal Replacement Therapy Plus Letrozole Incorporation Versus Letrozole Mild Ovarian Stimulation in Endometrial Preparation for Frozen Embryo Transfer: A Randomised Controlled Trial

Conditions
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IVF

Intervention / Treatment
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* Drug: estradiol valerate and letrozole
* Drug: letrozole 2,5 mg tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged between 18 and 37 years with either regular cycles or oligomenorrhoea or amenorrhoea. Women undergoing FET cycles. Participants should have at least one good-quality blastocyst available for vitrification and also for transfer after warming. Participants having optimal endometrium before starting luteal phase support Exclusion Criteria: Women who will refuse to participate in in the study. Women who will not reach the optimal endometrium. Participants that don't have at least one good-quality blastocyst for transfer after warming. PGT embryos will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 37 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (HRT plus letrozole incorporation)<br>Exogenous oestradiol in the form of 2 mg oral oestradiol valerate , three times daily will be started on the 2nd or 3rd day of the cycle. Tri-laminar endometrium of ≥ 9 mm will be the targeted cut-off. If the endometrium does not yet reach the target, oestradiol supplementation will be continued with serial US assessment until the targeted cut-off will be reached. Upon reaching the target endometrium, oral letrozole tablets 2.5 mg will be started twice daily for 5 days only with continuation of 6 mg daily oestradiol supplementation. Then, daily intramuscular progesterone in oil (100 mg intramuscular progesterone) will be started once per day with continuation of 6 mg oestradiol interventions: Drug:estradiol valertae Drug :letrozole 2.5 mg tablet | Drug: estradiol valerate and letrozole<br>* hormone replacement therapy by estradiol valerate plus letrozole incorporation .<br>|
| Active Comparator: Group B (Letrozole mild ovarian stimulation)<br>Oral letrozole 2.5-5 mg daily on cycle day(3-7) will be added . TVS will be performed from cycle day 8-10 to make sure that a dominant follicle has been recruited with the endometrium thickness ≥ 7 mm . Upon reaching the dominant follicle (18-20mm) , endometrial thickness will be measured on the day of ovulation trigger and blood sample will be withdrawn from each patient for assessment of E2 , P4 and LH levels. Patients with low LH level , high E2 level , low P4 level (<1 ng/ml) will continue in the RCT; 10,000unit HCG will be injected as ovulation trigger intervention : Drug :letrozole 2.5mg tablet procedure: on the day of ovulation trigger blood sample will be withdrawn from each patient for assessment of E2 , P4 and LH levels. | Drug: letrozole 2,5 mg tablet<br>* mild ovarian stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ongoing pregnancy rate (OPR) | Number of pregnant women with viable fetus at 12 weeks gestation per woman randomized | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate (CPR) | Number of gestational sacs with evident fetal pulsations per woman randomized,ectopic pregnancy is also includded pregnancy is aslo included | 5 weeks after embryo transfer | 
| Ectopic pregnancy | pregnancy outside the uterine cavity diagnosed by ultrasound ,surgical visualization or histopathology | 7 week | 
| Miscarriage rate | Number of miscarriages per woman with positive pregnancy tests | 12 weeks | 
| Implantation rate | Number of gestational sac recognized by ultrasound in uterus 3 weeks after embryo transfer | 21 days after embryo transfer | 
| live birth rate | The complete expulsion or extraction from a woman of a product of fertilization,after 22 complete weeks of gestational age;which,after such separation,breathes or shows any other evidence of life,such as heart beat,umblical cord pulsation or definite movement of voluntary muscles,irrespective of whether the umblical cord has been cut or the placenta is attached.A birth weight of 500 grams or more can be used if gestational age is unknown.Live births refer to the individual newborn ;for example,a twin delivery represents two live births | 22 completed weeks of gestational age | 
| Number of participants with Hypertensive disorders of pregnancy | gestational hypertension or preeclampsia | 20 weeks gestation till postpartum | 
| Number of participants with Large for gestational age | A birth weight greater than the 90th centile of the sex-specific birth weight for a given gestational age reference | from gestation till delivery |