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.