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Fertility and Cancer

More and more people are undergoing successful cancer treatment. After surviving a trying and emotionally exhausting regime which may include chemo/ radiotherapy and/or surgery, having to deal with fertility issues is difficult. Similarly for patients who have just been informed that they are in need of such treatment, future fertility potential can be the last thing on their minds. This article will explore the currently available fertility preservation options as well as those which may become available in the future. Fertility sparing surgery, being a separate issue, will not be discussed.

Male fertility preservation options

In this Unit we offer a semen preservation facility (sperm banking) together with supportive counselling. This enables men to have back up frozen sperm which can be accessed at a later stage. Emergency appointments are available to see fertility specialists who will advise the patients. At the appointment written information is provided and all required consents and screening blood tests organised. There is no limit on the storage time of frozen sperm however we suggest a review appointment after the first 10 years of storage.

Female fertility preservation options

Here the choices are dictated by the social situation as well as the time frame, imposed by necessity, to treat a newly diagnosed condition.

For women who are able to consider starting or extending a family, embryo creation and freezing via in vitro fertilisation offers the best currently available chance to conserve fertility. This option is available through Flinders Reproductive Medicine. In a young person chances of achieving a pregnancy are good, but multiple cycles may be needed. Even if permanent gonadal damage occurs, with embryos already created, endometrium can be prepared with the use of oestradiol valerate and progesterone. The Unit can see potential patients on an emergency basis and provide them with full counselling as well as written information. This option would always be considered in consultation with a primary treatment specialist as it involves a delay of up to 8 weeks (if more cycles are needed it could be up to 6 months). IVF treatment will also raise oestradiol to supra physiological levels which may have a detrimental effect on some malignancies. A natural IVF cycle avoids the rise in oestradiol but produces on average, only one oocyte.

Table 1: Risk of Ovarian Involvement by Various Cancers

Conceptually related to IVF and potentially available to all women, are oocyte freezing, immature oocyte freezing and IVM (in vitro maturation) and ovarian tissue freezing. Those options, discussed below, are still considered experimental and the best place for them to be employed is within a clinical trial.

Oocyte freezing requires the patient to go through a stimulated cycle and has its drawbacks. Despite improvement in freezing techniques, low post thaw survival, low fertilisation rates (despite intracytoplasmic sperm injection) and poor post implantation development make pregnancy rates significantly reduced compared to embryo freezing. With only about 150 pregnancies world wide reported from frozen oocytes there is obviously no long term birth outcome data.

Immature oocyte freezing with IVM is an option as it requires no hormonal stimulation and there is minimal delay to anticancer treatment; however the technique is still in the very early stage of development and there is no long term outcome data.

Another future option may be ovarian tissue freezing with orthotopic or heterotopic transplantation after the successful cancer treatment. Although pregnancy has been reported, there is no efficacy data and there are concerns about propagation of malignant cells.

Table 2: Options for Preserving Fertility in Women with Cancer

Ovarian chemo protection is another approach, not related to IVF technology. It has been used in patients being treated with cyclophosphamide. It stems from the observation that before menarche, cyclophosphamide does not seem to cause toxicity. However, during the reproductive years, premature ovarian failure (POF) was reported in half of all treated women after cyclophosphamide pulse therapy; affecting 100% of those older than 30 years, about 50% of patients between the ages of 20-30 years and 13% of patients younger than 20 years of age. The risk of gonadal damage is also directly related to the dosage of cyclophosphamide.

Alkylating agents are not cell-cycle-specific and thus do not require cell proliferation for their cytotoxic action. It is believed that they act on undeveloped oocytes and possibly on the pre-granulosa cells of primordial follicles. The gonadotropin-releasing hormone agonists have been efficient in young women in several non-randomized series. In lymphoma patients it was demonstrated in an observational study that 94% versus 44% had a regular menstrual cycle after treatment with GnRH-analogs.

A gap in randomized evidence will hopefully close with the initiation of the PREGO study (Prospective randomized study on protection against gonadal toxicity) in patients with SLE. In this study the authors are comparing randomized monthly injection versus no injection of gonadotropin-releasing hormone analogue (GnRH-A) to young SLE patients during cylclophosphamide therapy.

This form of treatment requires only minimal delay (2-3 weeks) before starting chemotherapy (as GnRH analogs have an initial flare up effect). This can be further discussed on a case by case basis with the clinicians in our Unit.

Oocyte Donation

As with other causes of premature ovarian failure, oocyte donation can offer a chance for a pregnancy and parenthood. Flinders Reproductive Medicine has written information and offers clinical and psychological expertise in supporting and treating couples who find themselves in this situation.

Adoption

Mentioned last, but for selected patients, adoption is a fulfilling option for establishing a family.
Although beyond the scope of our Unit, we nevertheless are able to provide counselling services, information and referral to our patients.

Children as Patients

A large study of childhood and adolescent cancer patients treated between 1945 and 1975 showed an adjusted relative fertility in survivors of 0.85 (95% confidence interval [CI]0.78 to 0.92) compared with that of their siblings. The adjusted relative fertility of male survivors (0.76 [CI] 0.68 to 0.86) was slightly lower than that of female survivors (0.93, 0.83 to 1.04). The most dramatic declines in relative fertility rates were in male survivors who had been treated with alkylating agents, with or without infradiaphragmatic irradiation.

In males who are sexually mature and mentally competent, sperm banking is an acceptable option. Germ cell preservation surgery is considered experimental. In females (unfortunately) all potentially available treatment options (harvesting of ovarian tissue or germinal vesicles) are considered experimental.

Summary

Patients who are faced with the sudden diagnosis of a malignancy or connective tissue disease requiring chemotherapy are often overwhelmed with all the new information and fertility issues are easily overlooked, contributing later to a sense of grief. Progress in the science means that new treatments are constantly being developed. New antagonists of apoptosis (like Sphingosine-1-Phoshate) are showing potential in animal studies, and alternative methods of ovarian stimulation (tamoxifen, aromatase inhibitors) are also on the horizon.
A discussion of available options and a holistic approach advocated by Flinders Reproductive Medicine will provide people with up to date advice tailored to their needs.

References

1. Gabor T Kovacs, Anthony J Rutherford and Donna Howlett. Fertility Preservation for Women O&G Vol 8, No 1 Autumn 2006.
2. Potential Options for Preservation of Fertility in Women. Rogerio A, Lobo MD. N Engl J Med 2005, 353:64-73.
3. Karin Manger, Ludwig Wildt, Joachim R Kalden, Bernhard Manger. Prevention of gonadal toxicity and preservation of gonadal function and fertility in young women with systemic lupus erythematosus treated by cyclophosphamide: The PREGO study. Autoimmunity Reviews 5 (2006) 269-272.
4. Blumenfeld Z, Avivi I, LinnS, Epelbaum R, Ben-Shahar M, Haim N. Prevention of irreversible chemotherapy induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing agonist in parallel to chemotherapy. Hum Reprod 1996; 11:1620-6.
5. Blumenfeld A. Preservation fertility and ovarian function and minimalization of chemotherapy associated gonadotoxicity and premature ovarian failure: the role of inhibin-A and -B as markers Mol Cell Endocrinol 2002; 187:983-105.

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