Clinical trial NCT05511272: The Circadian Variability of Serum Progesterone During the Day of a Frozen Embryo Transfer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fertility Disorders
Lead sponsor: Universitair Ziekenhuis Brussel
Sponsor class: OTHER
First posted: 2022-08-22
Enrollment: 44
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: The existence of circadian variability of serum progesterone during the day of a frozen embryo transfer
timeFrame: the day of the embryo transfer (from 8 am to 8 pm)
Secondary outcomes:
measure: Pregnancy outcomes after the frozen embryo transfer
timeFrame: from the day of the embryo transfer to 12 weeks of pregnancy
measure: The critical progesterone threshold to optimize pregnancy outcomes
timeFrame: from the day of the embryo transfer to 12 weeks of pregnancy
measure: The assessment of serum progesterone on the day of frozen embryo transfer
timeFrame: the day of the embryo transfer (from 8 am to 8 pm)
measure: Pregnancy outcomes after the frozen embryo transfer
timeFrame: from the day of the embryo transfer to 7 weeks of pregnancy
Other outcomes:
Locations:
city: Brussel
country: Belgium
facility: Brussels IVF
state: Jette
Study officials:
affiliation: Universitair Ziekenhuis Brussel
name: Christophe Blockeel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, Blockeel C. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017 Nov 1;32(11):2234-2242. doi: 10.1093/humrep/dex285.
citation: Melo P, Chung Y, Pickering O, Price MJ, Fishel S, Khairy M, Kingsland C, Lowe P, Petsas G, Rajkhowa M, Sephton V, Tozer A, Wood S, Labarta E, Wilcox M, Devall A, Gallos I, Coomarasamy A. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Fertil Steril. 2021 Dec;116(6):1534-1556. doi: 10.1016/j.fertnstert.2021.07.002. Epub 2021 Aug 10.
citation: Labarta E, Mariani G, Rodriguez-Varela C, Bosch E. Individualized luteal phase support normalizes live birth rate in women with low progesterone levels on the day of embryo transfer in artificial endometrial preparation cycles. Fertil Steril. 2022 Jan;117(1):96-103. doi: 10.1016/j.fertnstert.2021.08.040. Epub 2021 Sep 20.
citation: Wang Z, Liu H, Song H, Li X, Jiang J, Sheng Y, Shi Y. Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles. Front Med (Lausanne). 2020 Apr 8;7:104. doi: 10.3389/fmed.2020.00104. eCollection 2020.
citation: Labarta E, Rodriguez-Varela C, Mariani G, Bosch E. Serum Progesterone Profile Across the Mid and Late Luteal Phase in Artificial Cycles Is Associated With Pregnancy Outcome. Front Endocrinol (Lausanne). 2021 Jun 10;12:665717. doi: 10.3389/fendo.2021.665717. eCollection 2021.