Cycle-to-cycle Variability of Progesterone in the Endometrium in Patients Undergoing an Euploid Blastocyst Transfer in a Hormone Replacement Therapy (HRT) Cycle (PROMICOFET) (PROMICOFET)
This study looks at progesterone, a hormone that prepares the womb lining (endometrium) for pregnancy, in women having a frozen embryo transfer after IVF. Before an embryo is transferred, women take estrogen and progesterone medication to prepare the endometrium. Doctors currently check progesterone levels in the blood, but blood levels do not always match what is happening in the endometrium itself, and it is not yet known whether progesterone levels in the womb tissue stay the same from one treatment cycle to the next.
The study also looks at whether hormone levels relate to how the uterus contracts, to the bacteria naturally present in the vagina, cervix, uterus and gut, and to tiny particles released by cells (called extracellular vesicles) that may help the embryo and the womb "communicate" during implantation.
Participants are women who are already waiting for genetic test results on their embryos, a wait that typically lasts around 8 weeks. During this time, they go through two practice ("mock") treatment cycles using the same hormone medications as a real embryo transfer, but without an actual embryo. During these cycles, researchers collect blood and urine samples, a small tissue sample from the womb lining, swabs from the vagina, cervix and rectum, and a short ultrasound recording of womb movement. Afterwards, participants proceed with their real embryo transfer cycle, with similar (though fewer) measurements taken, and are followed to see whether they become pregnant.
The findings from this study may help doctors better understand how to personalize hormone treatment for future frozen embryo transfers, with the aim of improving pregnancy outcomes.
Study Overview
Status
Conditions
Intervention / Treatment
- Drug: Oestrogel® 0.75 mg (estradiol transdermal gel)
- Drug: Progesterone 200 mg vaginal capsules
- Procedure: Endometrial biopsy
- Procedure: Mock embryo transfer
- Procedure: Transvaginal ultrasound with uterine peristalsis assessment
- Procedure: Biological sample collection (blood, urine, vaginal/cervical/rectal swabs, follicular fluid, embryo culture media)
- Procedure: Embryo transfer catheter tip collection for bacterial DNA analysis
- Other: Questionnaires and pain assessment (VAS)
Detailed Description
This is a prospective, single-center pilot study conducted at the Department of Reproductive Medicine, Ghent University Hospital, in women undergoing preimplantation genetic testing for aneuploidy (PGT-A) prior to euploid blastocyst transfer in a hormone replacement therapy (HRT)-prepared frozen embryo transfer (FET) cycle. The pilot design was chosen because data on the interaction between endometrial and serum hormonal levels, the reproductive tract and fecal microbiome, uterine peristalsis, and embryo- and maternal-derived extracellular vesicles (EVs) in this setting are currently limited.
Each subject undergoes two mock HRT cycles during the approximately 8-week PGT-A waiting period, followed by one embryo transfer cycle. Endometrial preparation in each cycle consists of transdermal estradiol gel (Oestrogel®) until adequate endometrial thickness is reached, followed by vaginal micronized progesterone (Utrogestan®, 800 mg/day) for 6.5 days. In the mock cycles, no embryo is transferred; instead, study-specific procedures are performed, including endometrial biopsy for tissue hormonal quantification by UPLC-MS/MS, a mock embryo transfer with catheter tip collection for endometrial microbiome analysis, transvaginal ultrasound with speckle-tracking analysis of the uterine junctional zone to characterize contraction frequency, amplitude, and velocity before, during and after the procedure, and collection of vaginal, cervical and rectal swabs, urine, and blood for hormonal and extracellular vesicle profiling. The embryo transfer cycle follows the same sampling scheme (excluding endometrial biopsy) around an actual euploid blastocyst transfer performed under standard of care. Follicular fluid at oocyte pick-up and embryo culture media (collected on days 3 and 6 of embryo culture) are additionally retained for extracellular vesicle analysis, material that would otherwise be discarded during routine IVF laboratory processing.
Beyond the primary focus on intercycle reproducibility of endometrial tissue progesterone, the study explores associations between hormonal levels, uterine contractility, reproductive-tract and fecal microbiome composition, and extracellular vesicle cargo, with the broader aim of identifying candidate biomarkers of endometrial receptivity to inform future optimization of luteal phase support.
Given the established safety profile of the authorized study medications (Utrogestan® and Oestrogel®), adverse event and serious adverse event collection is selective, focused on events not attributable to standard-of-care fertility procedures; a Data Safety Monitoring Board was not deemed necessary.
Study Type
Enrollment (Estimated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Dominic Stoop, Prof. dr.
- Phone Number: +32 93321699
- Email: arg.studies@uzgent.be
Study Contact Backup
- Name: Paula Iglesias Moreno, MSc
- Phone Number: +32 93325631
- Email: paula.iglesiasmoreno@ugent.be
Study Locations
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-
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Ghent, Belgium, 9000
- Ghent University Hospital
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Principal Investigator:
- Dominic Stoop, Prof. dr.
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Contact:
- Paula Iglesias Moreno, MSc
- Phone Number: +32 93325631
- Email: paula.iglesiasmoreno@ugent.be
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Contact:
- Kathleen Wijnant, PhD
- Phone Number: +32 93324903
- Email: arg.studies@uzgent.be
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Age ≥18 and ≤40 years old.
- BMI ≥ 18 kg/m² and < 35 kg/m².
- Current pregnancy wish.
- PGT-A tested patients, undergoing a euploid blastocyst transfer in an artificial cycle.
- Dutch, French and/or English speakers, as informed consent forms (ICFs) are made in those three languages.
Exclusion Criteria:
- Known reasons for impaired implantation (specifically: presence of a hydrosalpinx; presence of a type I, II or III fibroid; Asherman's syndrome; uterine malformations; intrauterine adhesions; ≥ grade 3 endometriosis according to the ASRM classification, endometrial tuberculosis, adenomyosis).
- Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.
- Tumours of the ovary, breast, uterus, pituitary or hypothalamus.
- Untreated and uncontrolled thyroid dysfunction.
- Personal history of a thromboembolic event.
- Use of carbamazepine, rifampicin, phenytoin.
- Subjects unable to comprehend the investigational nature of the proposed study.
- Patients with a history of known thin endometrium (< 5 mm).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: HRT-Prepared FET with Endometrial and Biofluid Sampling
All enrolled participants undergo HRT endometrial preparation - transdermal estradiol gel (Oestrogel®) followed by vaginal micronized progesterone (Utrogestan®, 800 mg/day for 6.5 days) - across three consecutive artificial cycles: two mock cycles and one embryo transfer cycle, conducted during the standard-of-care waiting period for PGT-A results. In each mock cycle, participants undergo: endometrial biopsy, a mock embryo transfer (with catheter tip collection for microbiome analysis), transvaginal ultrasound (uterine peristalsis), and collection of vaginal, cervical and rectal swabs, urine, and blood samples for hormonal profiling and extracellular vesicle analysis. In the embryo transfer cycle, an actual euploid blastocyst is transferred under standard clinical care, with the same non-invasive study-specific sampling performed (excluding endometrial biopsy). Participants are followed for pregnancy outcomes. |
Oestradiol gel for endometrial preparation.
Two pumps need to be administered in the morning (between 6 and 8 am) and two pumps in the evening (between 6 and 8 pm).
In total, 3mg of estradiol per day.
Other Names:
Utrogestan®, 800 mg/day (in 200mg capsules) for 6.5 days
Other Names:
Pipelle-based endometrial tissue sampling performed during each of the two mock HRT cycles (not during the actual transfer cycle), for determination of tissue progesterone, estradiol (and where sufficient tissue remains, estrone and 17-OHP) by UPLC-MS/MS, and for derivation of organoids/cells for in vitro assays.
Other Names:
Catheter placement performed identically to a real embryo transfer but without loading an embryo, conducted during each mock cycle.
The catheter tip is collected (rather than discarded) for endometrial microbiome analysis.
Other Names:
Standardized 4-minute transvaginal ultrasound recordings performed before, during and after the (mock) embryo transfer in each of the three cycles, using speckle-tracking analysis of the junctional zone to quantify uterine contraction frequency, amplitude, velocity, coordination and direction.
Other Names:
Study-specific collection of: blood samples for hormonal profiling (estradiol, estrone, progesterone, 17α-hydroxyprogesterone) and extracellular vesicle (EV) analysis; urine samples for EV isolation; vaginal, cervical, and rectal swabs for microbiome analysis; follicular fluid collected at oocyte pick-up (otherwise discarded in routine care); and embryo culture media collected on days 3 and 6 of culture - all for EV composition and cargo analysis.
Other Names:
Collection of catheter tips following embryo transfer (study cycle) and, separately, from 30 routine clinical embryo transfers in non-enrolled patients, for protocol optimization of bacterial DNA extraction and endometrial microbiome analysis.
Other Names:
Patient-completed questionnaires on dietary habits and lifestyle (to support microbiome data interpretation) and a Visual Analogue Scale (VAS) pain-scoring questionnaire completed at the time of each (mock) embryo transfer.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Endometrial hormonal concentrations
Time Frame: For an individual patient: mock embryo transfer cycles 1 and 2. Approximately 8 weeks. For the whole study: through the study completion, approximately 2 years since start of recruitment.
|
Endometrial biopsies will be taken in mock embryo transfer cycles 1 and 2, on the day of mock transfer (day 6 after progesterone administration).
This tissue will be sent to the clinical biology department in the hospital UZ Gent, to perform UPLC-MS/MS and obtain the concentration of progesterone, estradiol, estrone, 17α-hydroxyprogesterone in the tissue.
This will later be correlated with the other outcome measurements: hormonal levels in blood, microbiome composition, uterine peristalsis, EV composition, etc.
The concentrations will be obtained in ng/ml or μg/ml.
|
For an individual patient: mock embryo transfer cycles 1 and 2. Approximately 8 weeks. For the whole study: through the study completion, approximately 2 years since start of recruitment.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Hormonal levels in blood
Time Frame: From OPU (oocyte pick-up day) until pregnancy follow-up visit (between 6 and 8 weeks of gestation)
|
Analysis of progesterone, oestradiol, oestrone and 17-alphahydroxyprogesterone concentration in blood and correlation with endometrial levels.
|
From OPU (oocyte pick-up day) until pregnancy follow-up visit (between 6 and 8 weeks of gestation)
|
|
Microbiome composition
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
Microbiome composition in the vagina, cervix, uterus and rectum; via swabs and embryo transfer catherter tip.
The samples will be collected on the day of (mock) embryo transfer through the three identically prepared HRT cycles.
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On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
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Clinical pregnancy outcomes: biochemical pregnancy
Time Frame: Follow-up pregnancy visit (6-8 weeks of gestation)
|
Clinical pregnancy outcomes will be measured with percentage of patients that reach: - Biochemical pregnancy: if no gestational sac was seen in the ultrasound during the follow-up pregnancy visit (6-8 weeks of gestation), but there is a positive blood or urine test measuring human chorionic gonadotropin (hCG). |
Follow-up pregnancy visit (6-8 weeks of gestation)
|
|
Clinical pregnancy outcomes: live birth
Time Frame: Follow-up pregnancy (6-8 weeks of gestation) until live birth (up to approximately 40 weeks after embryo transfer)
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Clinical pregnancy outcomes will be measured with percentage of patients that reach: - Live Birth Rate: The delivery of a live infant after 24 to 28 weeks of gestation, considered the gold-standard endpoint in fertility trials. |
Follow-up pregnancy (6-8 weeks of gestation) until live birth (up to approximately 40 weeks after embryo transfer)
|
|
Clinical pregnancy outcome: miscarriage
Time Frame: From the follow-up pregnancy (6-8 weeks of gestation) visit until miscarriage happens (before 22 completed weeks of gestational age).
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Clinical pregnancy outcomes will be measured with percentage of patients that reach: - Miscarriage Rate: The spontaneous loss of a verified clinical pregnancy before 22 completed weeks of gestational age |
From the follow-up pregnancy (6-8 weeks of gestation) visit until miscarriage happens (before 22 completed weeks of gestational age).
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Clinical pregnancy outcome: clinical pregnancy
Time Frame: Follow-up pregnancy visit (6-8 weeks of gestation)
|
Clinical pregnancy outcomes will be measured with percentage of patients that reach: - Clinical Pregnancy: Confirmed by ultrasound at 6-8 weeks showing a heartbeat or gestational sac, distinguishing it from a purely chemical (biochemical) pregnancy detected only by blood or urine hormone tests. |
Follow-up pregnancy visit (6-8 weeks of gestation)
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Questionnaire about lifestyle and dietary habits for better analysis of microbiome composition
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
This questionnaire mostly has questions that can be answered with YES/NO, being the remaining questions a multiple choice questions, or a fill in question (mostly if they check "yes" and we need more information, for example if they said they used antibiotics in the last 30 days, to ask which product, dose and duration of the treatment, and until when).
The data will be expressed as percentage of patients answering "yes", or percentage of patients selecting each option (in multiple choice questions).
|
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
|
Visual Analogue Scale (VAS) for (mock) embryo transfer
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
Visual Analogue Scale (VAS) for pain assessment during (mock) embryo transfer procedures.
The VAS score goes from 0 to 10, being 0 no pain, and being 10 the worst pain.
|
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
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Uterine waves/peristalsis analysis - contraction coordination
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
One of the uterine waves parameters we will obtain is the contraction coordination, which represents if anterior and posterior walls move synchronously or asynchronously to each other.
A higher value shows decreased coordination.
It does not have units but it is expressed in mean squared error.
This will be assessed before, during and after embryo transfer by 4-minute TVUS video recording.
|
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
|
Uterine waves/peristalsis analysis - contraction velocity
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
One of the uterine waves parameters we will obtain is the contraction velocity, which analyses at which speed do the waves propagate in a certain direction (F2C or C2F). This is obtained by first analysing the radial strain signal in the spatiotemporal frequency domain (20 seconds) and then averaging the velocities over time in the corresponding direction (C2F or F2C). A high value represents increased velocity in that direction. It is expressed in mm/s. This will be assessed before, during and after embryo transfer by 4-minute TVUS video recording. |
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
|
Uterine waves/peristalsis analysis - contraction direction
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
One of the uterine waves parameters we will obtain is the contraction direction, which explains whether the wave propagates fondus to cervix (F2C) or cervix to fondus (C2F).
It has no units.
Positive value is F2C, negative value is C2F and a value of 0 is a movement without predominant direction (opposing contractions).
This will be assessed before, during and after embryo transfer by 4-minute TVUS video recording.
|
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
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Uterine waves/peristalsis analysis - contraction amplitude
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
One of the uterine waves parameters we will obtain is the contraction amplitude, which reflects the strength of uterine contraction.
It is obtained by calculating SD of the strain signal in the longitudinal and radial directions from its frequency spectrum.
It has no units.
This will be assessed before, during and after embryo transfer by 4-minute TVUS video recording.
|
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
|
Uterine waves/peristalsis analysis - contraction frequency
Time Frame: On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
One of the uterine waves parameters we will obtain is the contraction frequency, which is the amount of contractions per minute (unit of measurement contractions/minute).
This will be assessed before, during and after embryo transfer by 4-minute TVUS video recording.
|
On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.
|
|
EVs composition in blood, follicular fluid and urine (maternal), and embryo culture media
Time Frame: From OPU (oocyte pick-up day) until pregnancy follow-up (between 6 and 8 weeks of gestation)
|
EVs cargo and composition analysis and RNA sequencing
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From OPU (oocyte pick-up day) until pregnancy follow-up (between 6 and 8 weeks of gestation)
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Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Health Care Quality, Access, and Evaluation
- Investigative Techniques
- Epidemiologic Methods
- Specimen Handling
- Clinical Laboratory Techniques
- Diagnostic Techniques and Procedures
- Diagnosis
- Punctures
- Surgical Procedures, Operative
- Data Collection
- Health Care Evaluation Mechanisms
- Quality of Health Care
- Public Health
- Environment and Public Health
- Polycyclic Compounds
- Pregnanes
- Steroids
- Fused-Ring Compounds
- Estrenes
- Estranes
- Estradiol Congeners
- Gonadal Steroid Hormones
- Gonadal Hormones
- Pregnenediones
- Pregnenes
- Reproductive and Urinary Physiological Phenomena
- Corpus Luteum Hormones
- Progesterone Congeners
- Urinary Tract Physiological Phenomena
- Estradiol
- Progesterone
- Surveys and Questionnaires
- Blood Specimen Collection
- Urination
- Utrogestan
Other Study ID Numbers
- ONZ-2023-0403
- B6702024000267 (Other Identifier: Commissie voor medische ethiek U(Z) Gent)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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