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

Official title

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

Overview

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.

Interventions

• 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 ultrasoun
• 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)
• 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)
• 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

Primary outcome measures

• Endometrial receptivity [Time frame: through study completion, an average of 2 years]

Secondary outcome measures (1)

• Senescent Cell Pathological Accumulation [Time frame: through study completion, an average of 2 years]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Spain · 1 center

• IVI-RMA Valencia Clinic — Valencia

Publications

• Aplin JD, Stevens A. Use of 'omics for endometrial timing: the cycle moves on. Hum Reprod. 2022 Apr 1;37(4):644-650. doi: 10.1093/humrep/deac022. PMID 35147196
• Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 2020 Dec 1;34(23-24):1565-1576. doi: 10.1101/gad.343129.120. PMID 33262144
• Boretto M, Cox B, Noben M, Hendriks N, Fassbender A, Roose H, Amant F, Timmerman D, Tomassetti C, Vanhie A, Meuleman C, Ferrante M, Vankelecom H. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development. 2017 May 15;144(10):1775-1786. doi: 10.1242/dev.148478. Epub 2017 Apr 25. PMID 28442471
• Boretto M, Maenhoudt N, Luo X, Hennes A, Boeckx B, Bui B, Heremans R, Perneel L, Kobayashi H, Van Zundert I, Brems H, Cox B, Ferrante M, Uji-I H, Koh KP, D'Hooghe T, Vanhie A, Vergote I, Meuleman C, Tomassetti C, Lambrechts D, Vriens J, Timmerman D, Vankelecom H. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat Cell Biol. 201 PMID 31371824
• Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update. 2003 Nov-Dec;9(6):515-22. doi: 10.1093/humupd/dmg045. PMID 14714588
• Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, Muter J, Lucas ES, Yamada T, Woods L, Lucciola R, Hou Lee Y, Takeda S, Ott S, Hemberger M, Quenby S, Brosens JJ. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife. 2017 Dec 11;6:e31274. doi: 10.7554/eLife.31274. PMID 29227245
• Burton GJ, Jauniaux E, Charnock-Jones DS. Human early placental development: potential roles of the endometrial glands. Placenta. 2007 Apr;28 Suppl A:S64-9. doi: 10.1016/j.placenta.2007.01.007. Epub 2007 Mar 8. PMID 17349689
• Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019 Jul 15;366:l2381. doi: 10.1136/bmj.l2381. PMID 31307997

Identifiers

NCT: NCT06280560 · 2109-FIVI-087-FD · PI23/00860

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗