Future potential of in vitro maturation including fertility preservation

Abstract

In several mammalian species, oocytes from small antral follicles after in vitro maturation (IVM) are successfully used for procreation. Humans are the exception, mainly because of limited access to immature oocytes and because oocyte maturation is uniquely regulated in women. With the introduction of cryopreservation of the ovarian cortex for fertility preservation, immature oocytes from small antral follicles in the medulla are now available for developing IVM on the basis of actual human studies. This review presents recent findings in favor of developing human IVM, including the oocyte diameter, follicle size from which the immature oocytes are collected, necessary level of follicle-stimulating hormone and luteinizing hormone to accelerate IVM, and secretion of factors from the cumulus-oocyte complex that affect the way oocyte maturation takes place. Furthermore, on the basis of studies in human granulosa cells and follicle fluid collected during the final maturation of follicles in vivo, a number of signal transduction pathways and hormone levels active during physiological conditions have been identified, providing new candidates and ways to improve the current IVM platform.Furthermore, it is suggested that the small droplet of culture medium in which IVM is performed mimics the hormonal milieu within a follicle created by the somatic cells and oocyte in vivo and may be used to advance oocyte nuclear and cytoplasmic maturation.Collectively, we envision that a continued research effort will develop a human IVM platform equally effective as for other mammalian species. In several mammalian species, oocytes from small antral follicles after in vitro maturation (IVM) are successfully used for procreation. Humans are the exception, mainly because of limited access to immature oocytes and because oocyte maturation is uniquely regulated in women. With the introduction of cryopreservation of the ovarian cortex for fertility preservation, immature oocytes from small antral follicles in the medulla are now available for developing IVM on the basis of actual human studies. This review presents recent findings in favor of developing human IVM, including the oocyte diameter, follicle size from which the immature oocytes are collected, necessary level of follicle-stimulating hormone and luteinizing hormone to accelerate IVM, and secretion of factors from the cumulus-oocyte complex that affect the way oocyte maturation takes place. Furthermore, on the basis of studies in human granulosa cells and follicle fluid collected during the final maturation of follicles in vivo, a number of signal transduction pathways and hormone levels active during physiological conditions have been identified, providing new candidates and ways to improve the current IVM platform. Furthermore, it is suggested that the small droplet of culture medium in which IVM is performed mimics the hormonal milieu within a follicle created by the somatic cells and oocyte in vivo and may be used to advance oocyte nuclear and cytoplasmic maturation. Collectively, we envision that a continued research effort will develop a human IVM platform equally effective as for other mammalian species. In response to the midcycle surge of gonadotropins, final oocyte maturation takes place in preovulatory follicles, which leads to the ovulation of a fully mature oocyte capable of sustaining further development. The transition of oocytes to the fully mature stage includes the following: nuclear maturation, from the prophase of the first meiotic division (i.e., the germinal vesicle [GV] stage) to the metaphase of the second meiotic division (i.e., metaphase II [MII] stage), and cytoplasmic maturation, which encompasses changes in the oocyte cytoplasm required to sustain chromosomal rearrangements, epigenetic modifications, and fertilization as a whole. For several mammalian species except humans, assisted reproduction is performed by aspirating immature GV oocytes from small antral follicles (SAFs), often ex vivo, which have received no ovarian stimulation with exogenous hormones. Robust protocols for in vitro maturation (IVM) of immature oocytes with subsequent in vitro fertilization (IVF) treatment have now resulted in high-efficacy methods with healthy offspring. This reflects many years of studying the regulation of oocyte maturation in easily accessible oocytes from rodents and larger domestic species (1Coticchio G. Dal Canto M. Mignini Renzini M. Guglielmo M.C. Brambillasca F. Turchi D. et al.Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization.Hum Reprod Update. 2015; 21: 427-454Crossref PubMed Scopus (293) Google Scholar, 2Robker R.L. Hennebold J.D. Russell D.L. Coordination of ovulation and oocyte maturation: a good egg at the right time.Endocrinology. 2018; 159: 3209-3218Crossref PubMed Scopus (87) Google Scholar, 3Roelen B.A.J. Bovine oocyte maturation: acquisition of developmental competence.Reprod Fertil Dev. 2019; 32: 98-103Crossref PubMed Scopus (5) Google Scholar). Only recently have human immature oocytes become available for such studies, where the introduction of cryopreservation of the ovarian cortex from young women for fertility preservation has increased the accessibility of human immature oocytes. Frequently, 1 of the 2 ovaries is surgically removed, and only the primordial follicles, primarily positioned in the cortex, are procured for freezing, whereas the surplus medulla, which is normally discarded, now forms the basis for collecting immature oocytes from SAFs with a diameter mainly ranging from 0.5 to 3 mm. In addition, immature oocytes are aspirated from SAFs with a diameter ranging from 3 to 8 mm. This has allowed a new approach to human IVM, which resembles that of other species and initiated the development of a more scientifically based platform for human IVM. The aim of this review is to delineate the current knowledge on the regulation of human oocyte maturation from SAFs and present a rationale for a new human IVM platform that accounts for the accelerated maturation in vitro compared with in vivo. In our view, fertility preservation providing access to immature oocytes now allows human IVM to be studied in more detail and paves the way for the development of new strategies that will advance human IVM to become clinically applicable. To advance human IVM, parameters important for oocyte maturation need to be defined. Normally, human oocytes are classified as immature oocytes provided that they are in the GV stage (or are in the process of transition to the MII stage), irrespective of the diameter of the oocyte the follicle from which the oocyte is the oocyte from the somatic and the developmental of oocytes in with the oocytes from follicles with a diameter of a be to a developmental compared with from preovulatory follicles as during to sustain nuclear maturation and cytoplasmic maturation. the of immature oocytes is on the diameter of the follicle from which they are collecting oocytes from the medulla in with fertility preservation, it is to the diameter of the follicle from where the oocyte and it is the oocyte diameter reflects the follicle In in humans, the oocyte diameter is only to the diameter in to many other species of follicle and oocyte diameter in mammalian species and PubMed Scopus Google Scholar, M. development in the human PubMed Scopus Google Scholar, D. et al.Oocyte diameter the maturation of human immature oocytes collected ex Reprod PubMed Scopus Google Scholar). that the human oocyte final diameter at the antral oocytes collected from SAFs with a diameter of on a diameter of to that of fully oocytes collected during treatment D. et al.Oocyte diameter the maturation of human immature oocytes collected ex Reprod PubMed Scopus Google that in humans, is the and oocyte it has been that the human oocyte diameter is and with the to sustain MII transition during IVM D. et al.Oocyte diameter the maturation of human immature oocytes collected ex Reprod PubMed Scopus Google Scholar). This that fully human immature oocytes from SAFs have the to sustain nuclear maturation and provided that cytoplasmic maturation be in favor of developing human IVM. This is by studies on human ovaries performed by of ovarian development in and PubMed Scopus Google that human follicles with a diameter 2 and of and whereas follicles with a diameter of a and The in the follicle to the follicle-stimulating hormone where follicles a with This that oocytes are more from healthy follicles the diameter of the follicles is mm. This with follicles, which become available from the medulla during fertility immature oocytes from SAFs in vitro are to conditions that by to oocyte may be This will be on the which the oocyte will be this may to the cytoplasmic maturation in this oocytes with a for In several mammalian species, oocyte maturation has been studied and levels of have been mainly in the to be of for of and oocyte maturation (1Coticchio G. Dal Canto M. Mignini Renzini M. Guglielmo M.C. Brambillasca F. Turchi D. et al.Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization.Hum Reprod Update. 2015; 21: 427-454Crossref PubMed Scopus (293) Google Scholar). oocytes have been from the antral it is to from in the oocyte for to oocytes from from such the of maturation is to This with immature human oocytes from where the of maturation at a in oocytes irrespective of they by cells in vitro maturation and of human germinal vesicle oocytes from PubMed Scopus Google Scholar, M. in vitro maturation of oocytes to ovarian cryopreservation in of Reprod PubMed Scopus Google Scholar, D. et of is during IVM of ex vivo collected human Reprod PubMed Scopus Google that the level is as important for the regulation of oocyte maturation in as in in that in with other pathways during oocyte meiotic and are the of and in the of meiotic in Reprod Dev. PubMed Scopus Google Scholar). 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