Impact of IVF Hormonal Therapy on Endometrial Receptivity and Endometrial Senescent Cell Pathological Accumulation (HormoSenoRec)

February 25, 2025 updated by: Fundación IVI

Impact of Controlled Ovarian Stimulation and Luteal Phase Support on Endometrial Receptivity and Endometrial Senescent Cell Pathological Accumulation: Pilot Study

Both controlled ovarian stimulation (COS) and frozen embryo transfer has become an integral part of in vitro fertilization (IVF) treatment. Fresh embryo transfer is usually performed by providing Luteal Phase Support (LPS) with progesterone after COS. Frozen embryo transfer (FET) is usually performed in artificial cycles with hormone replacement treatment (HRT), in which exogenous progesterone is administered, although it can also be performed in a Natural Cycle (without hormone supplementation) (NC). There is evidence that the supraphysiologic levels of estradiol and progesterone during COS+LPS and HRT could lead to morphologic and biochemical endometrial modifications, altering endometrial receptivity and lowering implantation and pregnancy rates.

We hypothesize that the supraphysiologic hormone levels required for both COS+LPS, and HRT may be inducing alterations in endometrial composition and function, specifically the chronic accumulation of senescent cells; either due to an excessive hormonal induction, a lack of clearance due to a deficit of uNKs, or a combination of both, ultimately affecting both endometrial receptivity and decidualization, worsening IVF outcomes.

The in vitro clearance of endometrial senescent cells by selective induction of apoptosis has been found to enhance the decidualization capacity of the rest of Endometrial Stromal Cells (EnSC), which could represent in a future adjuvant strategy to reduce the potentially deleterious effects of supraphysiologic hormone levels and improve reproductive outcomes in IVF patients.

The results derived from this project would have a direct impact on clinical practice. First, the results would allow us to evaluate, based on experimental data, potential endometrial side effects of stimulation protocols commonly used in IVF treatments. In addition, in the case of finding a pathological accumulation of senescent cells affecting endometrial receptivity, we will be able to in vitro evaluate the effectiveness of adjuvant senolytic (drugs designed to specifically remove senescent cells) compounds to in vitro improve the expression of endometrial receptivity markers, as a first step to demonstrate the effectiveness of their use in improving the reproductive outcomes of IVF patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Spain
      • Valencia, Spain, 46015

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

The study population will consist in 45 women undergoing IVF treatment for fertility problems and who, as indicated by their clinical practice, will be subjected to one of the following hormonal protocols (fifteen participants per group) (Natural Cycle, Controled Ovarian Stimulation + Luteal Phase Support, Hormone Replacement Therapy).

Additionally, as an endometrial receptivity reference group, we will recruit a population of 15 women with proven fertility belonging to the oocyte donation program in an endometrial cycle without hormonal stimulation (natural cycle).

The 60 participants will be recruited at the IVI-RMA Valencia clinic (Valencia).

Description

Study group (subfertile IVF patients).

  • Inclusion Criteria: Women aged 18-45 years, BMI ≥ 18.5- 30.
  • Exclusion criteria: Women presenting any uterine disease that affects the endometrial cavity, or with a thin or irregular endometrium, altered karyotypes, thrombophilias, or uncorrected systemic or endocrine diseases will be excluded.

Endometrial receptivity reference group (oocyte donors).

  • Inclusion criteria: women aged between 18 and 35 years, BMI ≥ 18.5- 25.
  • Exclusion criteria: Any cases of DIU presence, hormonal contraceptives at least during the last three months, altered karyotypes, thrombophilias, or uncorrected systemic or endocrine diseases will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Natural Cycle (NC)
No hormonal stimulation
Procedure: Natural Cycle (NC)
No hormonal stimulation. From day 6 of the menstrual period, follicular growth will be evaluated. As soon as a follicle reaches 17mm in diameter, ovulation test strips will be provided to assess LH levels in the first morning urine. The participant will report the positive and will be scheduled for sampling seven days later. An endometrial biopsy and a blood sample will be obtained 7 days after LH peak (LH+7)
Controlled Ovarian Stimulation (COS) + Luteal Phase Support (LPS)
Hormonal fresh transfer protocol
Procedure: Controlled Ovarian Stimulation + Luteal Phase Support
Short COS protocol with GnRH antagonist followed by progesterone supplementation. Will be initiated after a negative vaginal ultrasonographic scans to define ovarian quiescence, on days 1 and 2 of the menstrual period. For ovarian stimulation, 150-225 UI /day of FSHrec (GONAL F) will be administered along or in combination with 75 UI/day of HMG (Menopur). From day 6 onwards, HMG/FSHrec will be administered on an individual basis according to the serum E2 levels and transvaginal ovarian ultrasound scans and GnRH antagonist (Orgalutran) 0.25 mg /day is introduced as soon as a follicle of 14 mms diameter has achieved. hCGrec (6500 IU, Ovitrelle) will be administered when 7 or 8 follicles with a maximum diameter of >17-18 mms will observed. 400 mg of micronized vaginal progesterone will be administered (200 mg twice a day vaginal route), during 5 days. An endometrial biopsy and a blood sample will be obtained 7 days after hCG administration (hCH+7)
HRT programmed artificial cycle
Delayed hormonal transfer protocol
Procedure: Hormonal Replacement Therapy programmed artificial cycle
6 mg of oestradiol orally administered starting the first day of the menstrual period, followed by an endometrial scan 10-days later, and when a 7 mms triple line endometrium has seen by vaginal ultrasound scan, 800 mg of micronized vaginal progesterone (400 mg twice a day vaginal route), during five days, will be added to the oestrogen therapy. An endometrial biopsy and a blood sample will be obtained on day 5 of progesterone administration (P+5)
Endometrial receptivity reference group
No hormonal stimulation
Procedure: Endometrial receptivity reference group
Recruited among women belonging to the oocyte donation program and will follow the procedures described above for the Natural Cycle group. No hormonal stimulation. From day 6 of the menstrual period, follicular growth will be evaluated. As soon as a follicle reaches 17mm in diameter, ovulation test strips will be provided to assess LH levels in the first morning urine. The participant will report the positive and will be scheduled for sampling seven days later. An endometrial biopsy and a blood sample will be obtained 7 days after LH peak (LH+7)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endometrial receptivity
Time Frame: through study completion, an average of 2 years
To evaluate in vitro (on cells) endometrial receptivity markers such as prolactin, Prolactin, IGFBP1, FOXO1, HOXA-10, CLU, SCAS5, DIO, VEGF, TGFβ, CD34, CD31, CD44, MMPs, IL-15, IL-11, IL-6, LIF, Glycodelin, β-catenin, ALCAM, IGF-1R, c-KIT, SMAD3, etc
through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Senescent Cell Pathological Accumulation
Time Frame: through study completion, an average of 2 years
To evaluate in vitro (on cells) the presence of senescence markers such as lipofuscin granules (SentraGor or Sudan Black B), NF-kB, p-16, p-21, p38, P-p38, p53, cGAS, STRING, γH2AX, carbonyl proteins, etc
through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundación IVI

Collaborators

Instituto Valenciano de Infertilidad, IVI VALENCIA

Investigators

  • Principal Investigator: Francisco Domínguez Hernández, PhD, IVI Foundation, Valencia, Valencia, Spain

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2024

Primary Completion (Estimated)

December 30, 2025

Study Completion (Estimated)

December 30, 2025

Study Registration Dates

First Submitted

February 15, 2024

First Submitted That Met QC Criteria

February 26, 2024

First Posted (Actual)

February 28, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

February 25, 2025

Last Verified

February 1, 2025

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 2109-FIVI-087-FD
  • PI23/00860 (Other Grant/Funding Number: Instituto de Salud Carlos III, co-funded by European Union)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Anonymized results from Single Cell Sequencing will be uploaded to public databases belonging to Gene Expression Omnibus-NCBI for free access by researchers.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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