Cycle-to-cycle Variability of Progesterone in the Endometrium in Patients Undergoing an Euploid Blastocyst Transfer in a Hormone Replacement Therapy (HRT) Cycle (PROMICOFET)

NCT07818278 | Not Yet Recruiting Phase 4

• 2 other identifiers: ONZ-2023-0403B6702024000267
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Fertility; Implantation, Embryo

Keywords

progesterone; extracellular vesicles; embryo implantation; microbiome; female tract microbiome; uterine peristalsis; cycle-to-cycle variability; FET; HRT cycle

Outcome Measures

Primary Outcomes (1)

• Endometrial hormonal concentrations

  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 Outcomes (14)

• Hormonal levels in blood

  From OPU (oocyte pick-up day) until pregnancy follow-up visit (between 6 and 8 weeks of gestation)

• Microbiome composition

  On the day of (mock) embryo transfer through the three identically prepared HRT cycles. Approximately 3 months per patient.

• Clinical pregnancy outcomes: biochemical pregnancy

  Follow-up pregnancy visit (6-8 weeks of gestation)

• Clinical pregnancy outcomes: live birth

  Follow-up pregnancy (6-8 weeks of gestation) until live birth (up to approximately 40 weeks after embryo transfer)

• Clinical pregnancy outcome: miscarriage

  From the follow-up pregnancy (6-8 weeks of gestation) visit until miscarriage happens (before 22 completed weeks of gestational age).

Study Arms (1)

HRT-Prepared FET with Endometrial and Biofluid Sampling

EXPERIMENTAL

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.

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)

Interventions

Oestrogel® 0.75 mg (estradiol transdermal gel) DRUG

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.

Also known as: estradiol, estradiol gel, transdermal oestradiol, oestrogel

HRT-Prepared FET with Endometrial and Biofluid Sampling

Progesterone 200 mg vaginal capsules DRUG

Utrogestan®, 800 mg/day (in 200mg capsules) for 6.5 days

Also known as: utrogestan, progesterone

HRT-Prepared FET with Endometrial and Biofluid Sampling

Endometrial biopsy PROCEDURE

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.

Also known as: endometrial sample, endometrial tissue, uterine lining biopsy

HRT-Prepared FET with Endometrial and Biofluid Sampling

Mock embryo transfer PROCEDURE

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.

Also known as: fake embryo transfer, practice embryo transfer

HRT-Prepared FET with Endometrial and Biofluid Sampling

Transvaginal ultrasound with uterine peristalsis assessment PROCEDURE

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.

Also known as: uterine waves, uterine peristalsis, vaginal ultrasound

HRT-Prepared FET with Endometrial and Biofluid Sampling

Biological sample collection (blood, urine, vaginal/cervical/rectal swabs, follicular fluid, embryo culture media) PROCEDURE

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.

Also known as: blood sample, blood, urine, urine sample, vaginal swab, cervical swab, fecal swab, follicular fluid, follicular fluid collection, embryo culture media, embryo culture media collection

HRT-Prepared FET with Endometrial and Biofluid Sampling

Embryo transfer catheter tip collection for bacterial DNA analysis PROCEDURE

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.

Also known as: embryo transfer catheter tip collection, ET catheter collection

HRT-Prepared FET with Endometrial and Biofluid Sampling

Questionnaires and pain assessment (VAS) OTHER

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.

Also known as: questionnaire, questions, vas score, pain assessment, vas scale, Visual Analogue Scale

HRT-Prepared FET with Endometrial and Biofluid Sampling

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University Hospital, Ghent: lead
• Besins Healthcare: collaborator

Study Sites (1)

Ghent University Hospital

Ghent, 9000, Belgium

Location

MeSH Terms

Interventions

Estradiol; Progesterone; Utrogestan; Blood Specimen Collection; Urination; Surveys and Questionnaires

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Urinary Tract Physiological Phenomena; Reproductive and Urinary Physiological Phenomena; Data Collection; Epidemiologic Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Central Study Contacts

Dominic Stoop, Prof. dr.

CONTACT

93321699; arg.studies@uzgent.be

Paula Iglesias Moreno, MSc

CONTACT

93325631; paula.iglesiasmoreno@ugent.be

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Identical hormone replacement therapy (HRT) cycles: endometrial preparation with transdermal estradiol gel (Oestrogel®, 3 mg/day), followed by vaginal micronized progesterone (Utrogestan®, 800 mg/day for 6.5 days)

Study Record Dates

• First Submitted: August 24, 2026
• First Posted: September 14, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): August 31, 2029
• Last Updated: September 14, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)