The LUTEAL Trial: Luteal Stimulation vs. Estrogen Priming Protocol

NCT04447872 | Unknown

• 1 other identifier: 20-0080
• Study Type: interventional
• Target: 142
• Locations: 1 country
• Sites: 1

Brief Summary

Ovarian reserve defines the quantity and quality of the ovarian primordial follicular pool. Diminished ovarian reserve (DOR) indicates a reduction in the quantity of ovarian follicular pool to less than expected for age. It is an important cause of infertility in many couples. To date, there is no clear consensus in the literature on the definition of diminished ovarian reserve, and it is unclear whether low oocyte yield results from an abnormal atresia rate of the follicle pool, or from a lower follicle pool at birth or whether it can just occur as a normal variation in the population. The ovarian response to controlled ovarian stimulation with gonadotropins (for example, for in vitro fertilization) is largely determined by the ovarian reserve, and there are numerous different ovarian stimulation protocols that are employed to try and increase the oocyte yield of a particular cycle. There is no consensus on which, if any, of these protocols are superior and preferred for patient with DOR. Luteal gonadotropin stimulation is a protocol of controlled ovarian stimulation (COS) for use in assisted reproductive technologies (ART) that has emerged over the past decade as an acceptable alternative to the classic follicular gonadotropin stimulation. The luteal estradiol patch protocol was introduced in 2005 in patients with poor response to controlled ovarian stimulation (COS) and to address the phenomenon of early follicle recruitment in patients with diminished ovarian reserve (DOR). Luteal gonadotropin stimulation can potentially achieve the same effect by initiating follicular recruitment for IVF prior to the body's own premature recruitment. Our hypothesis is that the luteal stimulation protocol and estradiol priming protocol are equivalent with regard to the outcome of number of mature oocytes retrieved. Patients who will be undergoing controlled ovarian stimulation and who have a diagnosis of diminished ovarian reserve will be considered for this trial, and enrolled if meeting all inclusion and no exclusion criteria.

Conditions

Infertility; Diminished Ovarian Reserve; IVF

Keywords

IVF; In Vitro Fertilization; DOR; Diminished Ovarian Reserve; Controlled ovarian stimulation

Outcome Measures

Primary Outcomes (1)

• Number of mature (Metaphase II) oocytes retrieved

  Mature oocytes, capable of being fertilized in vitro

  First day after oocyte retrieval

Secondary Outcomes (6)

• Number of oocytes cumulus complexes retrieved

  First day after oocyte retrieval

• Oocyte fertilization rate

  First day after oocyte retrieval

• Blastocyst development rate

  Day 5-7 following oocyte retrieval

• Cycle cancellation rate

  Within two weeks of cycle start

• Total FSH dosage (IU) used

  From the first day of injections, through the day of oocyte retrieval

Other Outcomes (4)

• Embryo ploidy status

  When biopsy results return, usually within four weeks after oocyte retrieval

• Implantation rate

  Two weeks post embryo transfer

• Clinical pregnancy rate

  Five to seven weeks post embryo transfer

Study Arms (2)

Luteal phase ovarian stimulation (LPOS)

ACTIVE COMPARATOR

Patients will present in the luteal phase, and will begin 150 IU hMG and 300 IU recombinant FSH daily, as well as oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH can then be titrated per patient response. Gonadotropin releasing hormone antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be started per criteria. Once patients are ready for ovulation trigger, 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU), will be administered. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.

Procedure: Timing of injectable gonadotropins

Luteal estradiol priming protocol

ACTIVE COMPARATOR

In the luteal phase, the patient will begin Estradiol patches 0.1mg QOD. She will also take daily Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) for three days. With menses, she will begin 150 IU hMG, 300 IU recombinant FSH daily, and oral Clomiphene citrate 100mg qd (for five days). FSH can be titrated per patient response. GnRH antagonist will be started per criteria. 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU) will be administered for ovulation trigger. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.

Procedure: Timing of injectable gonadotropins

Interventions

Timing of injectable gonadotropins PROCEDURE

Gonadotropins will with be started in the luteal phase or in follicular phase (preceded by Estradiol patches)

Luteal estradiol priming protocol; Luteal phase ovarian stimulation (LPOS)

Eligibility Criteria

• Age: 20 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Female aged 20 - 45
• Regular menstrual cycles between 21 and 40 days
• Presence of both ovaries
• Meets criteria for DOR by the recent ASRM/ACOG Committee Opinion
• antimüllerian hormone (AMH) value less than 1 ng/mL
• antral follicle count less than 5-7 and
• follicle-stimulating hormone (FSH) greater than 10 IU/L or
• a history of poor response to in vitro fertilization stimulation (fewer than four oocytes at time of egg retrieval).

You may not qualify if:

• Oocyte donation cycle
• Oocyte freezing cycle
• Current ovarian cyst \> 3cm
• Anovulatory or oligo-ovulatory (\<6 ovulation per year)
• Previous oophorectomy
• Exposure to cytotoxic or pelvic irradiation
• Planned aromatase inhibitor usage during current ovarian stimulation
• Sensitizing or ovarian stimulating therapy in the past one month
• Additional contraindications to this study re, as follows (because such patients cannot receive an estrogen patch):
• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of breast cancer
• Known or suspected estrogen-dependent neoplasia
• Active DVT, PE, or a history of these conditions
• Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
• Known anaphylactic reaction or angioedema with estradiol patches

Sponsors & Collaborators

• Northwell Health: lead

Study Sites (1)

Northwell Fertility

Manhasset, New York, 11030, United States

RECRUITING

Related Publications (4)

• Lin LT, Vitale SG, Chen SN, Wen ZH, Tsai HW, Chern CU, Tsui KH. Luteal Phase Ovarian Stimulation May Improve Oocyte Retrieval and Oocyte Quality in Poor Ovarian Responders Undergoing In Vitro Fertilization: Preliminary Results from a Single-Center Prospective Pilot Study. Adv Ther. 2018 Jun;35(6):847-856. doi: 10.1007/s12325-018-0713-1. Epub 2018 Jun 4.

  PMID: 29869107 BACKGROUND

• Zhang W, Wang M, Wang S, Bao H, Qu Q, Zhang N, Hao C. Luteal phase ovarian stimulation for poor ovarian responders. JBRA Assist Reprod. 2018 Sep 1;22(3):193-198. doi: 10.5935/1518-0557.20180045.

  PMID: 29931967 BACKGROUND

• Wei LH, Ma WH, Tang N, Wei JH. Luteal-phase ovarian stimulation is a feasible method for poor ovarian responders undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer treatment compared to a GnRH antagonist protocol: A retrospective study. Taiwan J Obstet Gynecol. 2016 Feb;55(1):50-4. doi: 10.1016/j.tjog.2015.07.001.

  PMID: 26927248 BACKGROUND

• Wu Y, Zhao FC, Sun Y, Liu PS. Luteal-phase protocol in poor ovarian response: a comparative study with an antagonist protocol. J Int Med Res. 2017 Dec;45(6):1731-1738. doi: 10.1177/0300060516669898. Epub 2017 Jan 16.

  PMID: 28661216 BACKGROUND

MeSH Terms

Conditions

Infertility

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Central Study Contacts

Baruch Abittan, MD

CONTACT

5165621735; babittan2@northwell.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Study Record Dates

• First Submitted: June 18, 2020
• First Posted: June 25, 2020
• Study Start: September 15, 2020
• Primary Completion: June 1, 2025
• Study Completion: June 1, 2025
• Last Updated: October 16, 2023

Record last verified: 2023-10

Locations

US (1)