Chemo- and radiation therapies used to treat cancer can have the unintended effect of making patients infertile. Clinically established fertility preservation methods, such as egg and embryo cryopreservation, are not applicable to all patients, which has motivated the development of strategies that involve ovarian tissue removal and cryopreservation before the first sterilizing treatment. To restore fertility at a later date, the early-stage follicles present in the tissue must be matured to produce functional oocytes, a process that is not possible using existing cell culture technologies. This review describes the application of tissue engineering principles to promote ovarian follicle maturation and produce mature oocytes through either in vitro culture or transplantation. The design principles for these engineered systems are presented, along with identification of emerging opportunities in reproductive biology.

/pdf/bioengineering-the-ovarian-follicle-microenvironment-6fj8rq0h6y.pdf

Bioengineering the Ovarian Follicle Microenvironment

PURPOSE: Advances in oncological treatment and in reproductive medicine have made family planning and fertility preservation after cytotoxic treatment more and more attractive. The attitude of patients towards fertility preservation is definitely positive. TECHNIQUES OF FERTILITY PRESERVATION: Basically, both medical treatments and invasive procedures are possible. Ovarian down-regulation by GnRH analogues is widely used and simple to perform, with little delay. However its efficacy has still not been definitely proven. Standard methods of ART require a stable partnership. Therefore, cryopreservation of unfertilized oocytes after hormonal stimulation might be better for most patients. In recent years, the introduction of new cryopreservation protocols allows acceptable results. Since hormonal stimulation is cycle dependent, it might cause a delay in oncologic treatment. New stimulation protocols, which can be initiated in every cycle phase are under investigation. Finally, ovarian biopsy and cryopreservation, followed by replantation might be an option. The first pregnancies and deliveries have been described. CONCLUSION: In most cases a multimodal approach must be offered to the patient. Most treatment modalities can be combined. To offer comprehensive treatment and allow the current techniques of fertility preservation to be evaluated, patients and doctors would benefit from networks such as like FertiProtekt, which guarantees nationwide patient support.

Preservation of Fertility in Patients with Cancer

Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse or the components of the ovary that are not ovarian follicles The ovarian stroma includes more general components such as immune cells, blood vessels, nerves, and lymphatic vessels, as well as ovary-specific components including ovarian surface epithelium, tunica albuginea, intraovarian rete ovarii, hilar cells, stem cells, and a majority of incompletely characterized stromal cells including the fibroblast-like, spindle-shaped, and interstitial cells The stroma also includes ovarian extracellular matrix components This review combines foundational and emerging scholarship regarding the structures and roles of the different components of the ovarian stroma in normal physiology This is followed by a discussion of key areas for further research regarding the ovarian stroma, including elucidating theca cell origins, understanding stromal cell hormone production and responsiveness, investigating pathological conditions such as polycystic ovary syndrome (PCOS), developing artificial ovary technology, and using technological advances to further delineate the multiple stromal cell types

/pdf/the-ovarian-stroma-as-a-new-frontier-31cnavvolv.pdf

The ovarian stroma as a new frontier

Cryopreservation and transplantation of ovarian tissue has proved to be a promising technique to safeguard fertility in cancer patients. However, with some types of cancer, there is a risk of transmitting malignant cells present in the cryopreserved tissue, so transplantation after disease remission is not advisable. To restore fertility in these patients, some research teams have been developing a transplantable artificial ovary, whose main goal is to mimic the natural organ. It should be composed of a matrix that encapsulates and protects follicles, as well as ovarian cells, which are necessary for follicle survival and development. This article reviews progress made in the creation of a transplantable artificial ovary and discusses future trends for its development.

The artificial ovary: current status and future perspectives

Anti-cancer therapy, particularly chemotherapy, damages ovarian follicles and promotes ovarian failure. The only pharmacological means for protecting the ovaries from chemotherapy-induced injury is gonadotrophin-releasing hormone agonist, but its efficiency remains controversial; ovarian transposition is used to shield the ovary from radiation when indicated. Until the late 1990s, the only option for fertility preservation and restoration in women with cancer was embryo cryopreservation. The development of other assisted reproductive technologies such as mature oocyte cryopreservation and in vitro maturation of oocytes has contributed to fertility preservation. Treatment regimens to obtain mature oocytes/embryos have been modified to overcome various limitations of conventional ovarian stimulation protocols. In the last decades, several centres have begun cryopreserving ovarian samples containing primordial follicles from young patients before anti-cancer therapy. The first live birth following implantation of cryopreserved-thawed ovarian tissue was reported in 2004; since then, the number has risen to more than 130. Nowadays, ovarian tissue cryopreservation can be combined with in vitro maturation and vitrification of oocytes. The use of cryopreserved oocytes eliminates the risk posed by ovarian implantation of reseeding the cancer. Novel methods for enhancing follicular survival after implantation are presently being studied. In addition, researchers are currently investigating agents for ovarian protection. It is expected that the risk of reimplantation of malignant cells with ovarian grafts will be overcome with the putative development of an artificial ovary and an efficient follicle class- and species-dependent in vitro system for culturing primordial follicles.

/pdf/female-fertility-preservation-past-present-and-future-3h2dkllfid.pdf

Female fertility preservation: past, present and future

The cryopreservation and autotransplantation of ovarian tissue is emerging as a powerful approach for preserving fertility. However, for cancer patients, it may not be possible to transplant ovarian tissue due to the risk of re-seeding disease. We investigated strategies for transplantation of individually isolated follicles to minimize the risk of re-introducing cancer cells present within the vasculature of ovarian stroma. Procedures for large-scale isolation of early-stage follicles and their encapsulation into fibrin hydrogels were developed. For in vivo validation studies, mice were ovariectomized and transplanted with encapsulated follicles into the ovarian bursa. A substantial increase in the number of secondary follicles was observed in the graft at 9 days after transplantation, and antral follicles by day 21, demonstrating primordial follicle recruitment into the growing pool. Initially, elevated follicle-stimulating hormone levels declined substantially by day 21, indicating feedback from the graft; presence of corpora lutea showed the graft's capability of restoring hormone cyclicity. Taken together, the transplanted follicles were able to engraft, mature, and restore ovarian function in an infertile mouse. This biomaterial may, thus, provide a platform for follicle transplantation with a low risk of cancer contamination and for developing strategies that preserve fertility for women facing a cancer diagnosis.

/pdf/fibrin-mediated-delivery-of-an-ovarian-follicle-pool-in-a-2cvtd0x45s.pdf

Fibrin-mediated delivery of an ovarian follicle pool in a mouse model of infertility.

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Fibrin-mediated delivery of an ovarian follicle pool in a mouse model of infertility.