Endometrial Compaction and Its Influence on Pregnancy Rate in Frozen Embryo Cycle Regimes

Study Overview
=================
Brief Summary
-----------------
For a pregnancy to occur, an euploid embryo at blastocyst developmental stage, a receptive endometrium and the synchrony of both is crucial. Many studies lately investigated the influence of the endometrial thickness and pattern on the artificial reproductive technology (ART) outcome, however, with conflicting results.

Detailed Description
-----------------
Further on, the measurement of the endometrial thickness was mostly performed either on the day of final oocyte maturation in stimulated cycles with fresh embryo transfer or on the day of progesterone administration in FET cycles. Progesterone is essential for the secretory transformation and compaction of the endometrium, prior to implantation. A recently published paper (Haas et al., 2019) however, evaluated the degree of endometrial compaction under the influence of progesterone in FET cycles and described, that a lack of certain endometrial compaction has a negative impact on the ongoing pregnancy rate. As in this study embryos of unknown ploidy status were transferred, the role of embryo ploidy on the outcome may bias the study results. In the herein presented study protocol we aim to investigate the influence of endometrial compaction in FET cycles in which euploid embryos are transferred. HYPOTHESIS: Lack of endometrial compaction after the start of progesterone leads to an impaired reproductive outcome.

Official Title
-----------------
Endometrial Compaction and Its Influence on Pregnancy Rate in Frozen Embryo Cycle Regimes

Conditions
-----------------
Endometrial Disorder, Infertility, Female, IVF, Pregnancy Early

Intervention / Treatment
-----------------
* Diagnostic Test: Blood test
* Diagnostic Test: Ultrasound


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women aged 18 years to 40 years with regular menses (26-34 days) Having 1 or 2 chromosomally normal cryopreserved blastocysts available for transfer after IVF / ICSI treatment First frozen-thawed transfer cycle Progesterone level < 1.5 ng/mL day of trigger injection in stimulation cycle from which embryos to be transferred were created. Exclusion Criteria: Polycystic ovarian syndrome Poor ovarian responder in accordance with Bologna criteria Uterine abnormality US / saline infusion sonohysterogram Previous dilatation & curettage (D&C) Hydrosalpinx Asherman syndrome History of endometriosis AFS ≥ 2 ICSI due to severe male factor with testicular sperm Any known contraindications or allergy to oral estradiol or progesterone. Discontinuation of HRT medication ( medication error in research HRT cycle ) Failure to detect ovulation in the research natural cycle Ovulation after day 20 in a natural cycle Duration of estradiol exposure ≥ 17 days and endometrium < 6mm Spontaneous ovulation in HRT artificial cycle

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Stimulated cycles<br>Ovarian stimulation will be performed by standard protocols. Stimulation medication dosage will be individualised prior to stimulation start according to the ovarian reserve parameters and during ovarian stimulation according to the ovarian response and the measured levels of E2 and progesterone (P4), in order to avoid progesterone elevation during late follicular phase. Final oocyte maturation will be achieved by administration of either 10.000 IU of hCG, 0.3 mg of GnRH agonist (Triptorelin) or dual trigger (hCG and GnRH-analogue), as soon as ≥ 3 follicles ≥ 17 mm are present. Oocyte retrieval will be carried out 36 hours after administration of the trigger. Embryos will undergo PGT-A at blastocyst stage and be vitrified thereafter. | Diagnostic Test: Blood test<br>* Mesurement of E2, P4, LH, FSH hormones<br>Diagnostic Test: Ultrasound<br>* Follicular measurement and endometrium measurement<br>|
| Artificial (HRT) Cycles<br>Start of estradiol valerate 4mg on day 2 of the cycle for three days. Increase E2 to 6mg on day 4 of E2 treatment. E2 dose may be increased according to clinician discretion based on endometrial thickness. Maximum time of E2 exposure will be 14 days. Transvaginally scan to monitor endometrial development and to exclude the presence of a dominant follicle. Serial measurements of serum LH, estradiol and progesterone levels. Commence the initial progesterone dose of 100mg at 22hrs (vaginal suppository) after ≥ 7 days and ≤ 16 days of estradiol administration when the minimal endometrial thickness achieved is 6mm with a trilaminar appearance. Subsequently increase progesterone administration to 100mg vaginally three times daily. Continue estradiol administration 6mg (3 tablets daily). Blastocyst transfer is scheduled on the 5th full day of progesterone administration, following the initial initiation of progesterone. | Diagnostic Test: Blood test<br>* Mesurement of E2, P4, LH, FSH hormones<br>Diagnostic Test: Ultrasound<br>* Follicular measurement and endometrium measurement<br>|
| Spontaneous natural cycles<br>Ultrasound scans to monitor follicular growth and serial measurements of serum LH, estradiol and progesterone levels to determine the timing of ovulation. The LH surge will be considered to have begun when the concentration rises by 180% above the most recent serum value and continues to rise thereafter. Day 1 after the LH rise, a decrease in estradiol concentration is identified. Twenty four hours later progesterone concentrations rise with a level of greater than or equal to 1.5ng/ml confirming ovulation (day 0). This is considered as day 0 with initiation of vaginal progesterone 100mg (vaginal suppository) at 2200H. The following day (day 1) increases progesterone administration to 100mg vaginally three times daily (8 hourly) and continues this regime until 7 weeks gestation as per clinic protocol. Embryo transfer is scheduled 5 days (day 5) following confirmation of ovulation (day 0). | Diagnostic Test: Blood test<br>* Mesurement of E2, P4, LH, FSH hormones<br>Diagnostic Test: Ultrasound<br>* Follicular measurement and endometrium measurement<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rate | Ongoing pregnancy rate (≥ 12 weeks) in patients with endometrial compaction compared to patients without endometrial compaction after frozen embryo transfer of 1 or 2 euploid blastocysts | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical pregnancy rate in HRT cycle | Positive hCG, but at 5 gestational weeks no ultrasonographic visible gestational sac seen after embryo transfer in HRT-FET cycles with one or two euploid embryos, depending on the degree of compaction. | 5 weeks | 
| Biochemical pregnancy rate in spontaneous cycle | positive hCG, but at 5 gestational weeks no ultrasonographic visible gestational sac seen) after embryo transfer in NC-FET cycles with one or two euploid embryos, depending on the degree of compaction. | 5 weeks | 
| Clinical implantation rate in HRT cycle | Number of gestational sacs observed by ultrasound at 6 weeks of gestation divided by the number of embryos transferred), defined by a ß-hCG of > 5 IU on day 12 after embryo transfer in HRT-FET cycles with one or two euploid embryos, depending on the degree of compaction | 6 weeks | 
| Clinical implantation rate in spontaneous cycle | Number of gestational sacs observed by ultrasound at 6 weeks of gestation divided by the number of embryos transferred), defined by a ß-hCG of > 5 IU on day 12 after embryo transfer in NC-FET cycles with one or two euploid embryos, depending on the degree of compaction. | 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
infertilty, progesterone, endometrium, pregnancy