Old drugs: new eggs?

A recent presentation at a reproductive conference prompted wide media coverage, with headlines that seem to suggest that treatment with cancer drugs can 'grow new eggs' (see BioNews 872). This stems from a study by a team of scientists at the University of Edinburgh, led by Professor Evelyn Telfer, who reported that a small group of Hodgkin's lymphoma patients given a cocktail of chemotherapy drugs called AVBD (A - Doxorubicin (Adriamycin) B - Bleomycin V - Vinblastine D - Dacarbazine) did not suffer from infertility in the same way as patients given other cancer treatments. The Edinburgh team subsequently examined samples of the ovarian tissue from these patients and observed an increased number of follicles per ovary. The authors proposed that treatment with AVBD might stimulate the growth of new eggs.

Ten years ago, such a claim might have been met with incredulity as there was a long-held notion that women were born with a fixed egg reserve, the number of which decreases over time. However, emerging data from Telfer and others has raised the controversial possibility that ovarian stem cells (see BioNews 646) may be capable of providing new eggs in later life. With all assisted reproductive techniques relying on the provision of good quality oocytes, the potential for such a claim is huge.

In the most recent study, AVBD caused a two- to four-fold increase in follicular density in patients undergoing treatment for Hodgkin's lymphoma compared with age-matched healthy controls. This appears to be a striking increase; however, the sample size was small, with just eight patients on ABVD being compared with ten healthy controls. These patients showed a higher follicular density compared with the control patients and with an age-matched model for ovarian reserve. Three patients on another treatment for Hodgkin's lymphoma, OEPA-COPDAC, had lower follicular density compared with the controls.

Telfer stated that the follicular density represented that of prepubescent girls and that the oocytes appeared morphologically 'younger'. Viability and functionality, however, will be important to demonstrate whether these cells were genuinely stimulated from ovarian stem cells.

Importantly, ABVD represents a 'cocktail' of different chemotherapeutic drugs, therefore the mechanism of action is likely to be complex and multifactorial. With many cancer drugs targeting and destroying cells, there are considerable side effects, so the likelihood of applying these drugs to otherwise healthy sub-fertile patients undergoing assisted reproduction is low. Furthermore, if the conclusions are correct, the extent to which this treatment might work in non-cancerous patients is unclear – the pathways involved may be related to the condition in question. A wider consideration is whether such a treatment might have hitherto unpredicted side effects analogous to ovarian hyperstimulation (OHSS), a side effect seen with fertility-enhancing IVF drugs.

This study is, however, an interesting development that, when followed up by later studies, might present an exciting outlet for novel research in stimulating oocyte production. A critical demonstration will be in assessing patients before and after the treatment. If the growth of new eggs is identified, it will be important to carry out a comprehensive analysis of these oocytes and assess their viability and functionality. These findings will also require independent replication and verification that the eggs have been newly made as a result of the drugs in question. But at the very least this study does appear to offer strong support for the ovarian-sparing properties of AVBD.

If these patients truly are 'growing new eggs' this would be an exciting prospect – the lack of good quality oocytes is a major limitation within assisted reproduction. The idea of stimulating stem cells to follow a gamete-cell fate is not novel – both sperm and egg cells have been generated from stem cells and led to live births in mice. However, this has involved in vivo culture at the later stages of gametogenesis (see BioNews 619 and BioNews 676). Moreover, a recent study published in Nature demonstrated, for the first time, the successful recapitulation of the entire process of oogenesis in vitro using mouse stem cells by creating an in vitro ovary-like environment (1). While in the USA, biotech company OvaScience is investigating using these 'egg precursor cells' to supplement the oocytes of older patients or those with repeated lack of success in IVF with mitochondria.

While all this research is going on into how to make use of stem cells in reproductive medicine, it will be critical to undertake comprehensive investigations into how these oocytes function and to identify any risks before application to clinical practice. The difficulty with all these technologies is that any possible defects could have long-term or multi-generational effects. It is essential that the gametes derived from processes like this are shown to be fully functional – tested by their ability to give rise to fertilisation and live births, as well as showing the appropriate morphological, epigenetic and cellular profiles. The remaining big question is: how long does one follow up such offspring (and possibly their offspring) in order to be confident of safety?