Fertility after treatment for cancer

An increasing number of people are being successfully treated for cancer, and for those with an expectation of long-term survival the late effects of treatment are of concern. Young people have a particular interest in the impact of chemotherapy or radiotherapy on their future fertility, and recent media reports¹ of the successful transplantation of cryopreserved autologous ovarian tissue into a previously oophorectomised woman with non-malignant disease (K Oktay et al, Annual Meeting of American Society for Reproductive Medicine, Toronto, September 1999) will have caught the imagination of many. If a technique works in this situation, why not for a woman with malignancy whose ovarian tissue might be harvested before the start of sterilising chemotherapy?

Successful transplantation of cryopreserved ovarian cortical tissue into castrated ewes was first performed by Gosden and colleagues in 1994²: a return of oestrus cycles was observed, and, after normal mating, conceptions occurred and lambs were born. Further work in women suggests that small pieces of ovarian tissue can be successfully transplanted to an ectopic site within the pelvic cavity (A J Rutherford and R G Gosden, personal communication), and the recently reported case shows that an additional step (a freeze-thaw cycle) before transplantation is also possible.

Is the stage then set for the reversal of treatment induced sterility in women who have had cancer? The technique itself certainly appears to work, but several questions relevant to patients with cancer need answering: What are the indications for such an approach (not all treatments lead to permanent sterility)? How much tissue should be harvested and when? And, importantly, what is the risk of transmitting disease back into the patient at autotransplantation?

Since 1997, 10 young women at our centre have had ovarian tissue harvested and cryopreserved before receiving high dose chemotherapy for Hodgkin’s disease or non-Hodgkin’s lymphoma. In each case one whole ovary was removed by laparoscopic oophorectomy and the ovarian cortex (containing primordial follicles) removed en bloc, flattened, trimmed, and then cut into strips before being stored at liquid nitrogen temperature (J A Radford et al, British Cancer Research meeting, Edinburgh, July 1999). Histological assessment has shown varying numbers of primordial follicles and no evidence of disease, though minimal amounts might, of course, remain undetected by these methods, and the results of experiments in which ovarian tissue from patients has been xenografted into immune-deficient NOD/scid mice are, therefore, of great importance (S S Kim et al, annual meeting of American Society for Reproductive Medicine, Toronto, September 1999). If no evidence of tumour transmission is detected, reimplantation of ovarian cortical strips into patients is likely to follow soon afterwards.

Fertility after treatment for cancer is not only of interest to women. Men under the age of 55 have the option of cryobanking semen before the start of sterilising chemotherapy,³ but this is a finite resource, it does not permit a natural conception, and it is not an option for prepubertal boys. Furthermore, a recent study of 115 men who cryobanked semen before receiving treatment for Hodgkin’s disease showed that after prolonged follow up only 33 had used these stored gametes and, of those who did, only 8 were rewarded with a live birth (FH Blackhall et al, unpublished). It would appear, therefore, that this is not a very popular or successful way of achieving pregnancy and other strategies need to be considered.

In 1994 Brinster and colleagues in Philadelphia described how spermatogenesis could be reinstated in mice sterilised with busulphan by injecting their seminiferous tubules with a suspension of testicular cells derived from an allogeneic donor.⁴ These remarkable results suggested that human testicular cells might be harvested and cryopreserved before the start of chemotherapy and reintroduced into the testis on its completion. A clinical trial testing this hypothesis is currently under way in adults: 11 men have had testicular tissue harvested and cryopreserved as a single cell suspension (J A Radford et al, British Cancer Research meeting, Edinburgh, July 1999, and PF Brook et al, unpublished), and five who have now successfully completed treatment for cancer have had this material injected back into the donor testis. Results of follow up semen analysis are awaited with interest.

These developments and work in progress suggest that it may soon be possible to preserve the fertility of patients requiring treatment for cancer which ordinarily would lead to permanent sterility. Understandably, this makes exciting news but several important issues still need to be resolved and, until they are, the various techniques should be confined to ethically approved clinical trials where efficacy and safety can be fully evaluated. Although patient pressure is likely to be intense, we should proceed cautiously until we have a clearer view of the possible benefits and pitfalls. The alternative—the uncontrolled harvesting, cryopreservation, and reimplantation of gonadal tissue in a wide range of circumstances—may, at best, be ineffective or unnecessary and, at worst, life threatening.