Effect of GM-CSF on CAPA-IVM System Success Rates in PCOS

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

100 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-03-10

Study Completion Date

2022-12-31

Brief Summary

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In-vitro maturation (IVM) of human oocytes obtained from minimally stimulated or unstimulated ovaries offers a more "patient friendly" treatment option than the conventional Assisted Reproductive Technology (ART) treatment with controlled ovarian hyperstimulation (COH). However, maturation rate and the total blastocyst yield in oocytes undergoing in vitro maturation are still limited.

This pilot study aims to evaluate the addition of an important growth factor known as Granulocyte macrophage colony stimulating factor (GM-CSF). The investigators hypothesize that the addition of GM-CSF to human IVM culture media will increase pregnancy rates to comparable levels to that of IVF, making it a viable clinical option for couples undergoing assisted reproductive treatment.

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Detailed Description

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In-vitro maturation (IVM) of human oocytes obtained from minimally stimulated or unstimulated ovaries offers a more "patient friendly" treatment option than the conventional Assisted Reproductive Technology (ART) treatment with controlled ovarian hyperstimulation (COH).

Typically, IVM will be offered to women with polycystic ovaries (PCO/PCOS), or to patients with an excellent ovarian reserve, i.e. a high antral follicle count. IVM treatment is characterized by minimal administration of FSH or HMG and NO HCG ovulation trigger.

The IVM approach is less disruptive to patients' daily life through the reduced need for hormonal and ultrasound monitoring, avoids a range of minor and major complications, such as ovarian hyperstimulation syndrome, and aims to reduce the total cost of infertility treatment for the patient and for the health care budget.

Human oocytes retrieved from small antral follicles are able to resume meiosis by undergoing germinal vesicle breakdown and extrusion of the first polar body, if they have reached meiotic competence. These oocytes can be fertilized although only a proportion (less than 50%) of them can develop further into viable embryos. It has been hypothesized that failure of embryonic development may, at least in part, be due to an immature oocyte cytoplasm.

The investigators have developed a novel human in vitro maturation (IVM) culture system (named CAPACITATION-IVM , hereafter named "CAPA") using 1°) natural compounds known to influence cGMP and cAMP levels within the cumulus-oocyte-complex and 2°) compounds that are crucial for the oocyte-cumulus cross-talk. Keeping cyclic AMP high after retrieval in the GV oocyte prevents occurrence of nuclear maturation, enabling increased communication between the oocyte and the cumulus cells. This allows for the improvement in the synchronization of nuclear and cytoplasmic maturation processes in the oocyte, to the benefit of embryo quality.

The clinical outcomes of using CAPA-IVM in PCOS instead of fully stimulated GnRH-antagonist HP-HMG stimulated IVF-ICSI treatments showed equivalent live-birth rates after a first embryo transfer cycle done in artificial endometrial preparation in the two arms. Nevertheless, the CAPA-IVM cumulative live birth at 12 months was 44%, while in IVF it was 62,6. (Vuong et al., 2020). Hence the attrition rate of embryos in CAPA-IVM is larger than in conventional ART. In order to correct for this difference in good embryo number there is a need to refine the culture conditions.

This pilot study aims to evaluate the addition of an important growth factor known as Granulocyte macrophage colony stimulating factor (GM-CSF). In a recent breakthrough it has been shown that adding GM-CSF to IVM media can improve preimplantation embryo development in pigs, cattle and mice (unpublished results from Prof Mark Nottle, Adelaide University, Australia). Moreover, in mice, these improvements lead to an increased in implantation rate (+62%) and tended to increase birth rate (+25%) following the transfer of vitrified/warmed blastocysts compared with standard IVM. Based on these findings, this pilot study aims to determine the beneficial effect of using GM-CSF during the biphasic CAPA-IVM. The investigators hypothesize that the addition of GM-CSF to human IVM culture media will increase pregnancy rates to comparable levels to that of IVF, making it a viable clinical option for couples undergoing assisted reproductive treatment.

GM-CSF (Leukine in EmbryoGene medium, Medicult) has previously been used as an additive in embryo culture in order to increase the implantation rate of exposed embryos. This study in more than 1000 patients showed no advantage of adding GMCSF routinely. However in a subset of patients, those with poor implantation, the addition of this factor improved clinical results (Ziebe et al., 2013). In this study no safety issues were mentioned by exposing human oocytes during fertilization and early embryo formation.

In the intended study there will be only exposure of GM-CSF during the oocyte maturation steps, and the embryos will never be in direct contact with the investigational compound.

Conditions

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IVF PCOS IVM

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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GM-CSF group

Patients will be randomly allocated to intervention group with GM-CSF added to CAPA and maturation medium.

Following the 24h CAPA period, the evaluation of maturation (MII, GVBD, GV) will be done after 30 hrs IVM step.

Mature eggs are fertilized using Intracytoplasmic sperm injection (ICSI). Fertilized oocytes will be placed in a time-lapse incubator (ASTEC) and their development until the Day 5/6 (blastocyst formation) will be followed.

Group Type ACTIVE_COMPARATOR

GM-CSF group

Intervention Type OTHER

GM-CSF added to CAPA and maturation medium

Control group

Patients will be randomly allocated to control group without the addition of GM-CSF to CAPA and maturation medium.

Following the 24h CAPA period, the evaluation of maturation (MII, GVBD, GV) will be done after 30 hrs IVM step.

Mature eggs are fertilized using Intracytoplasmic sperm injection (ICSI). Fertilized oocytes will be placed in a time-lapse incubator (ASTEC) and their development until the Day 5/6 (blastocyst formation) will be followed.

Group Type ACTIVE_COMPARATOR

Control group

Intervention Type OTHER

GM-CSF will not be added to CAPA and maturation medium

Interventions

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GM-CSF group

GM-CSF added to CAPA and maturation medium

Intervention Type OTHER

Control group

GM-CSF will not be added to CAPA and maturation medium

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

* Diagnosed as PCOS using Rotterdam criteria (AFC=25 or the ovarian volume \>10ml)
* Agree to participate in the study

Exclusion Criteria

* No major uterine or ovarian abnormalities
* Endometriosis grade 2 or upper
* Severe OAT (concentration \<1 million/ml, motility \<10%), surgical sperm

Minimum Eligible Age

18 Years

Maximum Eligible Age

36 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes