Perspectives on the development and future of oocyte IVM in clinical practice

Abstract

Oocyte in vitro maturation (IVM) is an assisted reproductive technology designed to obtain mature oocytes following culture of immature cumulus-oocyte complexes collected from antral follicles. Although IVM has been practiced for decades and is no longer considered experimental, the uptake of IVM in clinical practice is currently limited. The purpose of this review is to ensure reproductive medicine professionals understand the appropriate use of IVM drawn from the best available evidence supporting its clinical potential and safety in selected patient groups. This group of scientists and fertility specialists, with expertise in IVM in the ART laboratory and/or clinic, explore here the development of IVM towards acquisition of a non-experimental status and, in addition, critically appraise the current and future role of IVM in human ART.

Keywords: Fertility preservation; In vitro maturation (IVM); Onco-fertility; Oocyte maturation; Polycystic ovary syndrome (PCOS).

Fig. 1

Landmarks in the development of human IVM. Major stages in the development of IVM beginning with studies using human oocytes and initial attempts at IVF and during 1990–2000 decades, first uses in the clinic, are shown. The last decade has witnessed modest expansion of clinical usage, especially in areas of onco-fertility and fertility preservation

Fig. 2

Differences between conventional IVF and IVM. The principal differences between conventional IVF and IVM are that in IVM cycles, patients receive minimal or no ovarian stimulation prior to OPU, oocytes are collected from small-medium sized antral follicles, and oocytes are meiotically matured in vitro from the germinal vesicle (GV) to metaphase II (MII) stage. Thereafter, mature IVM oocytes are treated exactly as per mature oocytes from conventional IVF. Adapted from [25]

Fig. 3

Oocyte–cumulus cell communication is fundamental to IVM success. Left, image of human MII oocyte collected after conventional ovarian stimulation and prior to removal of cumulus cells; note extensions from corona cells towards the oocyte surface. Confocal projection on the right is of an immature germinal vesicle (GV) stage bovine oocyte illustrating compact corona cells (top) sending numerous transzonal projections (arrow) that terminate on the oocyte cell surface. Alexa 555-phalloidin was used to label actin filaments in confocal image

Fig. 4

Major IVM protocols. A The original IVM protocol [8], where immature, GV-stage COCs are matured in vitro in one step to MII. Patients may or may not receive prior FSH priming as in either case all oocytes are at the GV stage at OPU. B A biphasic IVM protocol is a small variation on standard IVM, the notable difference being the additional pre-IVM culture step. Here, meiosis of immature cumulus-enclosed oocytes is deliberately arrested for ~ 24 h, before moving COCs into a meiosis promoting medium. Examples include the SPOM- and CAPA-IVM protocols. Patients may receive prior FSH priming, but not hCG priming, as the latter is incompatible with the need for intact compact COCs in this platform. C Patients receive a bolus of hCG prior to OPU, +/− prior FSH priming. A proportion (~ 10–20%) of oocytes are collected at the MII stage, some resume meiosis in vivo but are not mature (germinal vesicle breakdown (GVB) or MI), and the majority of oocytes are at the GV stage. The different stages of meiosis at OPU necessitate differing treatment in the laboratory: MII require fertilization on the day of OPU, whereas the maturing and immature oocytes require IVM culture. D This is the maturation in vitro of immature GV-stage oocytes collected from conventional IVF cycles after OS and ovulation triggering, mostly with hCG [38]. These are commonly regarded as medically unusable oocytes and are usually discarded in most IVF clinics [39]. These oocytes are usually naked, as oocytes are denuded of cumulus cells after OPU prior to ICSI; hence, rescue IVM oocytes are invariably cultured in a denuded state from the GV to MII stage in vitro