Oocyte maturation. Basic and clinical aspects of in vitro maturation (IVM) with special emphasis of the role of FF-MAS.

In Vitro maturation (IVM) of human oocytes is an emerging infertility treatment with great promise. To be successful this future assisted reproductive technology must entail both nuclear and cytoplasmic maturation of the oocytes and give rise to human embryos that have the same developmental potential as embryos resulting from the golden standard of human IVF. The aspiration of immature oocytes from small to medium size antral follicles followed by their maturation In Vitro present an attractive alternative to the hormonal stimulation of patients in In Vitro fertilization (IVF) treatment, since administration of exogenous hormones is a costly treatment and may cause severe health problems. Of the long list of side effect and health concern ovarian hyper-stimulation syndrome (OHSS) is by far the most severe although long term effect on cancer prevalence is another concern. Another potential group of patients that could benefit from future IVM treatments are the young women undergoing anticancer therapy (radiation- or chemotherapy). Thus, ovarian and oocyte cryopreservation techniques are emerging, however such treatments can only be fully realized when IVM becomes an efficient means of obtaining healthy birth. At present, the In Vitro maturation techniques are highly successful in mice, variable successful in domestic species and still regarded experimental in the human clinic due to suboptimal fertilization rates and embryo quality. This review discusses comparative studies of the processes of oocyte maturation In Vivo and In Vitro, in various mammalian species including human. Among the substances that have been reported to influence oocyte maturation there is an interesting endogenous signaling molecule: FF-MAS (4,4-dimethyl-5 alpha-cholest-8,14,24-trien-3 beta -ol), an intermediate in the cholesterol biosynthetic pathway present in all cells. This review gives special focus to FF-MAS, the effect seen in animal and human studies so far and its potential use in treatment of human infertility is being discussed, including both the safety and efficacy issues that need to be addressed. It is being reviewed how FF-MAS and related MAS analogues by our group and other scientific groups have been observed to mediate a dose-dependant response on both the nuclear maturation and especially the cytoplasmic maturation during oocyte maturation In Vitro thus giving rise to pre-embryos of higher developmental potential. Studies are reviewed regarding the family of meiosis activating sterols, its In Vivo regulation by gonadotropins (especially LH) and suggestions to the signaling pathways as the putative MAS receptor eliciting the important cytoplasmic maturation signaling cascade that involves mos/MAP kinase. The pharmacological effect of synthetic FF-MAS has been observed in various models and species, including murine, porcine and humane oocytes. Finally, the chromosome status of IVM human oocytes has been the focus of a large prospective clinical trial, documenting that FF-MAS acting on human oocytes during In Vitro maturation presents a safe procedure evaluated on numerical chromosome aberration rates in metaphase-II oocytes. In conclusion the In Vitro maturation of human oocytes is already now a valuable clinical treatment alternative for a subset of infertile patients, especially the Polycystic Ovarian Syndrome (PCOS) patients. IVM has the promise of being tomorrow's gold standard in treatment of human infertility if most of the important components of oocyte maturation are understood and can be adequately addressed In Vitro. Considering the present low frequency of successful fertilization and pre-implantation development following In Vitro maturation of human oocytes, the addition of FF-MAS or MAS analogues to the maturation medium to improve the cytoplasmic maturation and to yield higher quality pre-embryos may prove highly beneficial.