Fertility Preservation in Women With Malignancy: Future Endeavors

Abstract

The area of fertility preservation is constantly developing. To date, the only noninvestigational and unequivocally accepted methods for fertility preservation are cryopreservation of embryos and unfertilized oocytes. This article is one of several in a monogram on fertility preservation. The debate, pros and cons, and equivocal data on the use of GnRH analogues for fertility preservation are elaborated by 3 other manuscripts, in this monogram. A repeat of the arguments, pros and cons of this debatable issue, would be a repetition and redundancy of what is already included in this monogram. The subject of ovarian cryopreservation for fertility preservation is also elaborated by several other authors in this monogram. It is possible that, in the not too far future, the technologies of in vitro maturation of primordial follicles to metaphase 2 oocytes, and the "artificial ovary," will turn clinically available. These technologies may bypass the risk of resuming malignancy by autotransplantation of cryopreserved-thawed ovarian tissue in leukemia and diseases where malignant cells may persist in the cryopreserved ovarian tissue. We summarize here the suggested options for future endeavors in fertility preservation.

Keywords: Fertility preservation; GnRH analogues; chemotherapy; premature ovarian failure (POF); premature ovarian insufficiency (POI).

Figure 1.

Suggested pathophysiologic vicious cycle for explanation of the possible beneficial role of GnRHa in minimizing the gonadotoxic effect of chemotherapy. Alkylating agents such as cyclophosphamide destroy many follicles; therefore, the levels of estrogens and inhibins are reduced, bringing about an increase in FSH secretion, due to decreased negative feedback. The increased FSH recruits many follicles to enter the unidirectional path of folliculogenesis, to be destroyed by the alkylating agents. The GnRHa, by its effect to prevent increased gonadotropin concentration, may minimize this vicious cycle. The AMH may also play an important role in this pathophysiologic process. AMH indicates anti-Müllerian hormone; FSH, follicle-stimulating hormone.

Figure 2.

Schematic cartoon summarizing the possible future beneficial effects of various agents in minimizing the gonadotoxic effect of chemotherapy. In addition to the present modalities of GnRHa co-administration, cryopreservation of embryos, ova, or ovarian tissue, future endeavors may consist of the generation of gametes from induced pluripotent stem cells (iPC), in vitro maturation (IVM) of PMFs stored in the cryopreserved ovarian tissue, generation of an in vitro “artificial ovary,” and use of many possible agents. Such possible protective agents include AMH, tamoxifen, melatonin, Shilajit, resveratrol, imatinib (Gleevec), mangafodipir, sphingosine-1-phosphate (S1P), AS101, ceramide-1-phosphate (C1P), granulocyte colony-stimulating factor (G-CSF), dexrazoxane, and possibly others (???). AMH indicates anti-Müllerian hormone.

Figure 3.

The balance between ceramide and sphingosine-1-phosphate (S1P), the first inducing apoptosis and cell death, whereas the second induces cell growth. Therefore, the cells’ fate to die or survive and thrive depends on the balance between ceramide and S1P.