In vitro maturation is an attractive new approach to human assisted reproduction

The ability to obtain a large number of competent oocytes is one of the main goals of assisted reproductive technology. Since its clinical onset nearly 30 years ago, human in vitro fertilization (IVF) has depended on expensive gonadotropins to induce ovarian stimulation and oocyte maturation, which cost up to half of the total cost for this method of infertility treatment. Exogenous gonadotropins are used to rescue the growth of small follicles that would otherwise have been inhibited by the dominant one.

Furthermore, the use of gonadotropins and – after their introduction in the 1980s – the combination of gonadotropin-releasing hormone (GnRH) analogs with gonadotropin stimulation, has been associated with side effects, such as thrombosis or ovarian hyperstimulation syndrome (OHSS). OHSS still remains a risk for women and their pregnancies, with serious side effects leading to hospitalization. These circumstances have given rise to concerns regarding current IVF practice and everyone will agree today that there is a need to develop easier and cheaper alternatives for assisted reproduction.

In vitro maturation (IVM) involves aspiration of cumulus-enclosed immature oocytes from small antral follicles prior to atresia induction by the selected and dominant follicle and supporting their maturation from the germinal vesicle stage to the MII stage in vitro. The application of IVM to human oocytes is not new: pioneering work on human oocytes was published by Bob Edwards in the early 1960s [1]. However, it is mainly recently that IVM has attracted attention and undergone a rapid worldwide expansion as a modern alternative to IVF.

Especially in recent years, IVM has been developed extensively in order to provide a simpler approach to overcoming infertility. In a recent review, Jurema and colleagues summarized published studies and reported pregnancy rates per transfer of 21–53% in women with polycystic ovarian syndrome (PCOS) and 17–33% in normally menstruating women [2].

However, compared with conventional IVF, lower success rates indicate the need for more intensive research in this area. For fundamental developmental progress in IVM technology we need more information about the underlying endocrinology, developmental biology of ovarian follicles and the maturational processes of human oocytes in vivo and in vitro. Recent publications demonstrate progress in these fields, both clinically and theoretically. Today, IVM can be regarded as a clinically established and feasible technique that produces acceptable pregnancy rates, although several key questions remain unanswered.

Which patients should be offered IVM?

Various patient groups have been offered IVM in the past and recent studies illustrate the successful use of IVM in a broad range of infertility patients. Historically, IVM has been applied to women with PCOS and to women with polyfollicular ovaries based on ultrasound criteria owing to their higher numbers of oocytes and higher chances of obtaining competent oocytes after maturation. However, the technique has also been used in regularly menstruating women with normal-appearing ovaries, especially in cases of infertility based solely on male or tubal factor. However, this resulted in lower pregnancy rates.

IVM has been used as an alternative to cycle cancellation in patients at risk of developing OHSS. However, prospective randomized trials comparing IVM outcome with standard IVF in these subgroups have not been performed. Data comparing the efficiency of IVM with alternative options (coasting or triggering with GnRH agonists) in cases of imminent OHHS are lacking.

‘To prime or not to prime’: is gonadotropin priming necessary in IVM cycles?

Various protocol variations for IVM are now available for PCOS patients and regularly menstruating women. PCOS patients seem to benefit from follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) priming in order to overcome follicular arrest and induce oocyte maturation [3]. Data on regularly cycling women are more controversial. Whereas some authors reported that priming with FSH and hCG improved the outcome, others could not confirm these findings [4]. The question of using FSH- and even hCG-priming is still unanswered and further randomized prospective trials with sufficient case numbers are needed for clarification.

Meanwhile, various authors have reported successful IVM in the presence of a dominant follicle (natural cycle IVM–IVF), although the optimal timing of immature oocyte retrieval is still a matter of debate [5]. However, oocyte aspiration is usually performed when the leading follicle reaches 12 mm in diameter. Preliminary studies demonstrate that the development of a dominant follicle can be neglected.

What are the optimal culture conditions for immature oocytes?

The maturation period in vitro can be regarded as the ‘needle eye’ of IVM treatment. Too little information exists on how to manipulate and support oocyte maturation in vitro. As we know from experimental studies, desychronization between nuclear and cytoplasmic maturation by disruption of cytoplasmic maturation processes after removing the oocyte from its follicle compartment leads to a heterogeneous cytoplasmatic oocyte endowment. The fact that this compromises the developmental competence of in vitro-matured oocytes is still an unresolved problem with IVM.

One important aspect is the establishment of imprinting patterns during oocyte maturation. The inclusion of various sera in culture media may modify demethylation and remethylation in the oocyte genome and may produce offspring with imprinting disorders. However, data on disturbed human oocyte imprinting are still lacking.

Is IVM safe?

It has been estimated that, since its introduction, more than 1000 children conceived with IVM have been born worldwide. Recent reports indicate that the malformation rate and the early development of children conceived after IVM are comparable to non-IVM infants. Available data concerning the rate of congenital anomalies and neonatal and obstetric outcome are reassuring so far but, as the duration of follow-up is too short, more information is necessary before definitive conclusions can be drawn [6].

Conclusion: IVM is a patient-friendly approach warranting further evaluation

Despite lower success rates and various open questions, IVM is an attractive and patient-friendly approach owing to its various advantages. Even today, IVM has the potential to be an adjuvant to standard IVF technology since conventional controlled ovarian hyperstimulation leads to inconvenience, cost and unnecessary risks.

As optimal techniques will emerge with further research, the international expansion of IVM into many clinics will continue and additional positives of IVM practice will emerge, such as easier oocyte banking through the cryopreservation of immature oocytes prior to chemotherapy in cancer patients or simply to preserve fertility before older age.

In the long term, prospective research will uncover the fundamental mechanisms underlying early development of primordial and growing follicles. IVM can be regarded as the starting point of a fascinating perspective on assisted reproductive technology.