The Circadian Variability of Serum Progesterone During the Day of a Frozen Embryo Transfer

Study Overview
=================
Brief Summary
-----------------
Serum progesterone levels will be evaluated at four different time points during the day of an artificially prepared frozen embryo transfer cycle (HRT FET cycle) and a modified natural cycle frozen embryo transfer cycle (mNC FET cycle) (at 08:00, 12:00, 16:00 and 20:00).The pairwise percentage differences in serum progesterone levels for each patient will be calculated. The intra-day variability of progesterone will be analyzed using mixed models. Pregnancy outcomes will also be assessed. The sample size calculated consisted of 22 patients for the HRT-FET study and 22 patients for the mNC FET study.

Detailed Description
-----------------
In the HRT FET, estradiol valerate (Progynova) will be administered for endometrial preparation. If the endometrial thickness will be ≥ 6,5 mm during an ultrasound scan planned following an initial period of estrogen priming, micronized vaginal progesterone will be started (Utrogestan 800 mg/d). The transfer of a single blastocyst will be performed on the 6th day of progesterone administration. In a modified NC FET, there is no intake of medication but endocrine and ultrasound monitoring during the proliferative phase. Ovulation trigger with hCG will be considered when a dominant follicle between 16 and 20 mm will be observed and when the endometrial thickness will be ≥ 6,5 mm. The transfer of a single blastocyst will take place on the 7th day after hCG injection. Serum progesterone levels will be evaluated at four different time points during the day of an artificially prepared frozen embryo transfer cycle (HRT FET cycle) and a modified natural cycle frozen embryo transfer cycle (mNC FET cycle) (at 08:00, 12:00, 16:00 and 20:00). Pairwise percentage differences in serum progesterone levels for each patient will be calculated. The intra-day variability of progesterone will be analyzed using mixed models. Pregnancy outcomes will also be assessed.

Official Title
-----------------
The Circadian Variability of Serum Progesterone During the Day of a Frozen Embryo Transfer in an Artificially Prepared Cycle and in a Modified Natural Cycle

Conditions
-----------------
Fertility Disorders

Intervention / Treatment
-----------------
* Biological: blood test


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 and ≤ 40 years old BMI ≥ 18.5 and ≤ 25,9 kg/m2 The patient will undergo a hormone replacement therapy frozen embryo transfer cycle (HRT FET) or a modified natural cycle frozen embryo transfer cycle (mNC FET) according to the standard clinical practice in Brussels IVF In the HRT FET cycle the patient will be administered estradiol valerate and 6 days of micronized vaginal progesterone before the embryo transfer Adequate endometrial pattern (triple layer) and thickness (>6.5 mm) at the moment of planning of the transfer Single blastocyst embryo transfer Signed informed consent Non-smokers Exclusion Criteria: Age > 40 (women > 40 years old demonstrated an enhanced rate of absorption of progesterone using vaginal tablets compared to younger patients) BMI ≥ 26 (serum progesterone levels on the day of embryo transfer are lower in overweight and obese women compared to those with normal weight) Patients who need to take vaginal estradiol valerate during the HRT FET cycle Intake of any experimental drug or any participation in any other clinical trial within 30 days prior to study start Mental disability or any other lack of fitness, in the investigator's opinion, to preclude subjects in or to complete the study. Current or recent substance abuse, including alcohol and tobacco (patients who stopped tobacco usage at least 3 months prior to screening visit would be allowed) Refusal or inability to comply with the requirements of the study protocol for any reason, including scheduled clinic visits and laboratory tests. Embryo transfer after IVM cycle, PGT or oocyte acceptance Uterine pathologies (fibroids, polyps, chronic endometritis), uterine malformations (septum, Mullerian malformation) and hydrosalpinx

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

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Frozen embryo transfer cycle<br>Patients who will undergo a frozen embryo transfer in the modified natural cycle and in an artificially prepared cycle will be included | Biological: blood test<br>* four blood samples will be withdrawn from the participants during the day of their frozen embryo transfer cycle<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The existence of circadian variability of serum progesterone during the day of a frozen embryo transfer | To evaluate if there is significant variability in circadian level of serum progesterone on the day of an artificially prepared frozen embryo transfer cycle and during the day of a modified natural frozen embryo transfer cycle | the day of the embryo transfer (from 8 am to 8 pm) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy outcomes after the frozen embryo transfer | To evaluate the Clinical pregnancy rate (CPR) in patients who underwent HRT FET or mNC FET. CPR is defined as a pregnancy documented by ultrasound at 6-8 gestational weeks that showed a gestational sac in the uterus | from the day of the embryo transfer to 12 weeks of pregnancy | 
| The critical progesterone threshold to optimize pregnancy outcomes | To evaluate the critical threshold of serum progesterone on the day of the FET below which pregnancy rates are significantly lower | from the day of the embryo transfer to 12 weeks of pregnancy | 
| The assessment of serum progesterone on the day of frozen embryo transfer | To study when is the best moment to measure serum progesterone on the day of FET | the day of the embryo transfer (from 8 am to 8 pm) | 
| Pregnancy outcomes after the frozen embryo transfer | To evaluate the on going pregnancy rate (OPR) in patients who underwent HRT FET or mNC FET. OPR is defined as a viable pregnancy at the ultrasound taken at 12 weeks of gestation that shows the presence of fetal heartbeat | from the day of the embryo transfer to 7 weeks of pregnancy |