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

Recruiting

• Conditions: Endometrial Receptivity
• Interventions: Procedure: Natural Cycle (NC); Procedure: Controlled Ovarian Stimulation + Luteal Phase Support; Procedure: Hormonal Replacement Therapy programmed artificial cycle; Procedure: Endometrial receptivity reference group

• Registration Number: NCT06280560
• Lead Sponsor: Fundación IVI

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2024-02-01
• Study First Submitted: 2024-02-15
• Study First Submitted QC: 2024-02-26
• Study First Posted: 2024-02-28
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-25
• Last Update Posted: 2025-02-27
• Primary Completion: 2025-12-30
• Study Completion: 2025-12-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 60

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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Natural Cycle (NC)	Natural Cycle (NC)	No hormonal stimulation
Controlled Ovarian Stimulation (COS) + Luteal Phase Support (LPS)	Controlled Ovarian Stimulation + Luteal Phase Support	Hormonal fresh transfer protocol
HRT programmed artificial cycle	Hormonal Replacement Therapy programmed artificial cycle	Delayed hormonal transfer protocol
Endometrial receptivity reference group	Endometrial receptivity reference group	No hormonal stimulation

Primary Outcome Measures

Name	Time	Method
Endometrial receptivity	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

Secondary Outcome Measures

Name	Time	Method
Senescent Cell Pathological Accumulation	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

Trial Locations

Locations (1)

IVI-RMA Valencia Clinic; 🇪🇸 Valencia, Spain