Fertility preservation for girls and young women with cancer: what are the remaining challenges?
Authors: W. H. B. Wallace, R. D. Barr
Journal: Human Reproduction Update (2010)

The excellent and balanced article by Jadoul et al., in this issue of HRU, reviews the available evidence for fertility preservation in girls and young women at risk of a premature menopause. Importantly, they also present their own experience of ovarian cryopreservation in 58 cases all under 16 years old. To date there have been at least 10 pregnancies worldwide after othotopic reimplantation of frozen–thawed ovarian cortex. The success rate is unclear as the denominator (the number of women in whom frozen–thawed ovarian tissue has been reimplanted) is unknown. There have been no pregnancies reported following the reimplantation of ovarian tissue harvested pre-pubertally, but with the accepted age-related decline from birth in the number of non-growing follicles, young children are potentially ideal candidates for this procedure (Wallace and Kelsey, 2010). Jadoul et al. demonstrate that it is safe and feasible to collect ovarian tissue for freezing, laparoscopically under a general anaesthetic, without complications and without delaying cancer chemotherapy. However, their case series clearly demonstrates the difficulty of giving an accurate prognosis for fertility before treatment starts, for this may change as the disease and therapeutic requirements evolve. Patients classified initially as low risk for a premature menopause (Wallace et al., 2005a) may become high risk later if they relapse. Acute lymphoblastic leukaemia is the commonest childhood malignancy with around 80% of patients becoming long-term survivors. First-line treatment of these patients is associated with an excellent prognosis for future fertility. Not only will the survivors of first-line therapy be able to have their own children naturally, but their offspring also are not at increased risk of congenital abnormalities or cancer in childhood. However, those patients who relapse after first-line treatment may require conditioning treatment with total body irradiation (TBI) and myeloablative chemotherapy, and a bone marrow transplant from an HLA-matched donor. TBI is likely to be sterilizing (Wallace et al., 2005b), and in children will affect uterine development (Critchley et al., 2005). The uterus is at significant risk of damage following abdominal, pelvic or total body irradiation, in a doseand age-dependent manner. The clinical consequences are increased risk of miscarriage and premature delivery (Sanders et al., 1996). In the case of a young patient with a pelvic sarcoma, who will require alkylating agent-based chemotherapy and radiation to the pelvis, the likelihood of a premature menopause is high (Wallace et al. 2005b) and, clearly, ovarian cryopreservation should be considered. However, radiation-induced damage to the uterus and surrounding structures may impair the ability of the uterus to carry a pregnancy to term (Critchley and Wallace, 2005). It remains important that these issues are discussed before treatment starts, as it is not recommended to attempt harvesting of ovarian tissue once treatment has begun (Lee et al., 2006; Anderson et al., 2008a). The option of harvesting ovarian tissue or freezing harvested eggs remains if the patient relapses and is due to receive potentially sterilizing chemo-radiotherapy, there is sufficient time, and the patient’s health and general condition are satisfactory. With advances in in vitro growth and maturation of non-growing follicles (Telfer et al., 2008), it remains entirely possible that, in the not-too-distant future, reimplantation of ovarian tissue will not be necessary and fertilization of cryopreserved mature oocytes will be possible in vitro. The advantage of avoiding reimplantation is the avoidance of the risk of recrudescence of the original cancer, which may have been present in the stored tissue and survived cryopreservation (Rosendahl et al. 2010). It is imperative that harvested ovarian tissue should be examined pathologically to exclude the very real possibility of contamination of the material by malignant cells from the original cancer. This is a particular concern for haematological cancers, but is a potential concern for all cancers (Abir et al., 2010). It is important to be aware that reimplantation of ovarian cortical tissue is a separate procedure at a time distant from the treatment of the original cancer. Consent for harvesting ovarian tissue from children often will have been obtained from their parents, whereas informed consent for reimplantation can be obtained from the patients at a much later date when they are competent to assess the complex issues themselves. Should a whole ovary be removed, as advocated by Andersen et al., (2008), or are cortical strips sufficient as is the majority practice (Anderson et al., 2008a; Jadoul et al., 2010)? The most important consideration is primum non nocere (first do no harm). If it remains difficult to predict which patients are at high risk of an early menopause, then conservative surgery seems sensible. However, laparoscopic