Introduction

In 2001, 625,000 women in the USA were afflicted with invasive cancer. By 2010, 1/250 adults will be childhood cancer survivors. While damage is reversible in other tissues (bone marrow, gastrointestinal tract and hair follicles, the number of germ cells is fixed since fetal life and cannot be regenerated. Due to the rapid advances in cancer care, the majority of children, adolescents and young adults with cancer can now expect to be cured and become long-term survivors. Due to the increased life expectancy of those with cancer, quality of life issues are assuming increasing importance in the planning and delivery of cancer treatment. Previously, discussions of life expectancy superseded any conversations regarding future fertility. However, with increasing survival rates, this should no longer be the case. The effects of chemotherapy on future fertility are of paramount concern. Many treatment regimens are gonadotoxic and may thus negatively affect future childbearing potential. The spectrum of ovarian damage may range from transient amenorrhea to impaired fertility to irreversible premature ovarian failure with Sterility and all the clinical signs and symptoms of menopause.

Methods to reduce treatment-related gonadotoxicity are desperately needed. Modifying treatments to become less toxic regimens or administering agents to protect gonadal function during chemotherapy have been applied. The former is not always an option given the sensitivity of tumor cells to certain chemotherapeutic agents, and the relationship between the dosage of chemotherapy administered and the probability of cure. One must not sacrifice chances of survival for chances of future fertility. An important observation is that pre-menarchal girls have less gonadal damage from chemotherapy. The ovaries are thought to be quiescent prior to the onset of puberty. Thus, these pre-menarchal ovaries have lower levels of follicular activity, are down-regulated, and are theoretically more protected from the toxic effects of treatment as compared to those that are active. Currently, the choices for preserving fertility in chemotherapy patients are limited. One potential avenue for treatment has been the administration of agents for pituitary down-regulation to mimic the pre-menarchal ovary in hopes of protection. Other viable options for fertility preservation include in-vitro Fertilization with Cryopreservation of embryos for future transfer, ovarian tissue cryopreservation, ovarian transplantation, and Oocyte Vitrification.

Medical therapy – GnRH agonists and antagonists

GnRH analogues may offer some protection against ovarian failure in a select population of patients. Though the studies have only included small numbers of patients, they have demonstrated some benefit in preservation of ovarian function with the use of GnRH analogues prior to cancer treatment. It has been proposed that GnRH agonist and antagonist use prior to chemotherapy may have a protective effect via two mechanisms. First, by down-regulating the hypothalamic pituitary axis (HPA), they may reduce the number of primordial follicles destroyed by toxic agents. Second, GnRH agonists and antagonists may reduce the blood flow to the ovary and decrease the delivery of toxic chemotherapeutic agents. This second theory may also explain the lack of a protective effect with GnRH analogues on ovarian function observed with increasing chemotherapeutic dosages and provide explanation why this treatment has no effect with radiation therapy.

At this time, though the data seems promising with regard to GnRH analogues, small numbers of patients and short follow-up periods plague the studies. Thus, there is insufficient evidence to definitively recommend this therapy and further study is greatly needed.

Assisted Reproductive Technology (ART)

ART has been repeatedly demonstrated to be a viable option for fertility preservation in patients who have a partner or who are willing to use donor sperm. The ability to perform “emergency IVF” must be recognized by the IVF center and many accommodations must be made. It is therefore best to pursue this treatment in a large center that runs year-round and has the potential to go from a new patient visit to IVF as quickly as possible. Even with the best of centers, this therapy may necessitate a delay in treatment of two to four weeks. For patients with estrogen responsive tumors the Stimulation protocols can be tailored so as to not increase the estrogen level to the same degree that it would be elevated otherwise. In this select population, the risks of ovarian stimulation must be weighed carefully against the potential for cancer progression. It is very important to note that even with these limitations, the eventual success of this therapy is unparalleled and should be offered to all women as first-line therapy.

Ovarian Tissue Cryopreservation:

Surgical removal and cryopreservation of ovarian tissue prior to cytotoxic treatment has recently been described and holds promise as a future therapy. Cryopreserved tissue can either be subsequently be transplanted either to the pelvic area or to alternate locations, or the cryopreserved tissue can be thawed and made to mature in vitro so as to have mature oocytes that can then be used for in-vitro fertilization. There have been several cases of successful ovarian transplantation to date. The technology behind in-vitro follicular maturation is still under development but holds great potential for the future.
Ovarian tissue cryopreservation is an attractive alternative to IVF for fertility preservation because the time needed for ovarian stimulation is not required. There have been several reported live births from ovarian transplantation. There is only a small delay in cancer treatment. Furthermore, patients do not need to have a partner at the time of treatment and the tissue can remain frozen until the patient is ready for conception. Due to the large numbers of immature oocytes in the ovarian cortex, this method can also be used for premenarchal girls. The primary risk of ovarian tissue cryopreservation and subsequent transplantation is the potential for the tissue to contain cancerous cells and to re-seed the pelvis and cause recurrence

Unlike ovarian transplantation, in vitro follicular maturation does not require the tissue to be transplanted into the patients body. Instead, the ovarian tissue is harvested on a matrix rich in exogenous gonadotropins which enablesFollicle and oocyte maturation outside of the body and without risk to the patient. There are many barriers to be overcome in the development of this technology and the freezing of ovarian tissue for this reason is considered experimental and should only be performed under an IRB approved protocol.

Oocyte vitrification

Oocyte vitrification is an exciting, emerging technology that has the potential to aid in fertility preservation. Oocyte vitrification has the advantage over IVF with Embryo cryopreservation in that there are fewer ethical dilemmas with the storage of oocytes as compared to the storage of embryos. Additionally, this is an ideal option for a single woman as there is no need for either a male partner or for donor sperm. It does, however, carry some of the same disadvantages that are seen with IVF and embryo storage. Perhaps the largest impediment to success is the time required to undergo ovarian hyperstimulation and oocyte retrieval. This may require treatment delay of 2-4 weeks. In addition, for patients with estrogen responsive tumors, the increased estrogen levels associated with stimulation may not be an acceptable option.

Oocyte vitrification is an active area of research at FCI. We are actively recruiting patients under and IRB approved protocol for oocyte vitrification. At a cost that is greatly reduced from traditional IVF, a woman may choose to preserve her fertility with oocyte vitrification. This project has received support from EMD Serono who provides medications for ovarian hyperstimulation at no charge to our patients.

Conclusion

The ideal approach for cancer treatment would be to design treatment regimens that maintain high cure rates while decreasing or eliminating agents with significant tissue toxicity. If this were the case, the discussion regarding fertility preservation would be moot. However, until these regimens exist, we are obligated to offer methods for fertility preservation to all women with cancer or who require the use of radiation or chemotherapy for systemic disease.

Consultation regarding fertility preservation should be offered to all women prior to cancer therapy. A reproductive endocrinologist and Infertility specialist is the ideal person to offer consultation. Female patients and their families should be counseled regarding side effects of chemotherapy on ovarian function, as well as on methods to limit this damage.

·       Ovarian suppression with the use of GnRH analogues should be considered in all post-menarchal women prior to initiating therapy, as it may offer some benefit to preserve future fertility.

·       Patients who undergo chemotherapy and continue to menstruate should be closely followed for signs and symptoms of premature ovarian failure.

·       If a patient has a partner and is able to delay treatment by a few weeks, emergency IVF should be undertaken. This has the single greatest success rates for fertility preservation. · If a woman does not have a partner and is not interested in using donor sperm for the creation of embryos, then oocyte vitrification provides a viable alternative.

·       If the use of IVF or oocyte vitrification are not possible to due the inability to delay treatment or because of pre-menarchal status, ovarian cryopreservation can be offered if an IRB protocol exists.

·       Continuous developments will enable us to preserve and restore fertility in a growing number of cancer survivors. If these therapies should not be available or if offered and do not work, alternatives such as Oocyte Donation are excellent alternatives.