The artiﬁcial ovary: any new step is a step forward Several advances have come about during the last decade in the ﬁeld of fertility preservation. Cryopreservation of ovarian cortex and transplantation (COC-T) is probably the most relevant technique for patients who are not eligible to undergo oocyte or embryo vitriﬁcation. This procedure minimizes time lapses before oncologic treatments and allows the preservation of fertility in young prepubertal girls for whom controlled ovarian stimulation is not a valid option. Unfortunately, COC-T is not safe when there is an increased risk of reintroducing malignant cells, such as Burkitt's lymphoma or leukemia (1). At present, there is no clinical alternative for these kinds of patients to preserve their fertility, although there are several experimental approaches that aim to provide safe options. All of them focus on in vitro follicular growth and maturation, aiming to obtain mature and fertilizable oocytes without reintroducing the tissue back into the patient (2). Despite much progress, limitations for translation to a clinical setup still remain: viable embryos from in vitro–cultured follicles have never been produced in a species other than the mouse, mainly from cultures of activated follicles (3). Such limitations result from the fact that the development of the follicular unit is a complex and not completely clariﬁed process that requires the participation and interaction of the oocyte itself, the granulosa and theca cells, and the surrounding cells and matrix of the ovarian connective tissue. From activation of primordial follicles to the last steps of oocyte maturation after LH surge, the needs of the developing follicle change in terms of paracrine stimuli, both biochemical and mechanical (2). This evolving situation explains why follicular culture is not so easy, even with the use of multistep systems. In the study published by Luyckx et al. (4), the authors have designed an artiﬁcial ovary using a three-dimensional matrix to create a more physiological environment to promote follicular development. They employed highly biocompatible substances such as ﬁbrin and thrombin, supplemented by stromal cells to the matrix in which preantral follicles were encapsulated. These novel results represent another step forward in the development of techniques aiming to diminish the risk of malignant cell reintroduction after ovarian cortex retrieval and retransplantation in oncology patients. Taking into account the aforementioned problems related to safety and the difﬁculty of culturing follicles in vitro, the present paper has the important potential of translation to the clinical ﬁeld. There are several key points that could contribute to the success of the present study:  the use of ﬁbrin and thrombin to make the matrix biodegradable and therefore adaptable to the further potential needs of the follicle, which are different from those at the moment of isolation. The use of ﬁbrin has been proven to be effective in promoting follicular development when used for in vitro follicle growth in nonhuman primates (5);  the presence of somatic ovarian cells within the matrix. Such cells could promote follicular development and growth by being a source of paracrine signals; and  the use of an in vivo model together with the biodegradable nature of the matrix would allow for vascular invasion from the host 940
and potential recruitment of immune cells, which would help in the ﬁnal steps of follicular maturation. The exciting results of the present work open the door to new therapies in the ﬁeld of fertility preservation. Nevertheless, reasons for caution must be raised:  the authors propose to use the artiﬁcial ovary in patients at the risk of reintroduction of malignant cells; in a clinical situation, the source for follicles and stromal cells to build the artiﬁcial ovary would be the cryopreserved tissue of the patient, therefore, it should be mandatory to prove that such an artiﬁcial ovary is free of malignant cells.  There are some issues that could limit the present results from becoming a clinical reality: the growth rate and size of a human follicle differs from that of a mouse, so that further research using human tissue and immunodeﬁcient mice would be welcome.  The results presented in the paper are encouraging enough to keep working along such a line of research, but they are still basic and the follow-up is too short: oocyte competence must be proven, and fertilization, embryo development, and, of course, healthy offspring should be obtained in murine and nonhuman primates to prove the effectiveness of an artiﬁcial ovary. To what extent an in vivo model of follicular growth could contribute to solve the problems faced by the different in vitro approaches should be seen in the next few years. Whatever happens, the more options, the more likely it is that solutions will be found. Cesar Díaz-García, M.D. Sonia Herraiz, Ph.D. Grupo de investigaci on de Medicina Reproductiva, Instituto de Investigaci on Sanitario La Fe and Unidad de Preservaci on de la Fertilidad, Area de Salud de la Mujer, Hospital Universitario y Politecnico La Fe, Valencia, Spain http://dx.doi.org/10.1016/j.fertnstert.2014.01.057 You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/diazgarciac-artiﬁcial-ovaryfertility-preservation/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
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