Hope for restoring fertility in survivors of childhood cancer
A step forward for treating infertility in cancer patients
- Date : 06 Nov 2012
- Topic : Palliative and supportive care
A promising stem-cell-based approach for treating infertility has been successfully demonstrated in preclinical study, as reported in the November issue of the journal Cell Stem Cell. The work represents an important milestone for translating this strategy to the clinic, particularly for cancer survivors who have been rendered infertile by chemotherapy they received before reaching sexual maturity.
Cancer patients who undergo radiation therapy or chemotherapy often become infertile because these treatments damage dividing cells, including not only cancer cells but also spermatogonial stem cells (SSCs)—stem cells that develop into sperm. Prior to cancer therapy, adult men can cryopreserve their sperm and later use these cells to father children. But pre-pubertal boys don't have this option because they have not yet produced any mature sperm, so cancer treatments can leave them permanently infertile.
One promising strategy for these young patients is to preserve their SSCs before they undergo cancer therapy and later transplant these cells after they finish cancer treatment and reach sexual maturity. This approach has worked in a range of animal models, but past studies in large animals have primarily used radiation therapy to cause infertility, even though chemotherapy is also a common source of infertility in cancer patients.
To see whether it was possible to restore fertility using these cells, Dr. Orwig and his team biopsied the testes of pre-pubertal and adult male macaque monkeys and cryopreserved the cells from the small samples. The monkeys were then treated with chemotherapy agents known to impair fertility. A few months after chemotherapy treatment, the team re-introduced each monkey's own spermatogonial stem cells back in to his testes using an ultrasound-guided technique.
Sperm production was established from transplanted cells in nine out of 12 adult animals and three out of five pre-pubertal animals after they reached maturity. In another test, spermatogonial stem cells from other unrelated monkeys were transplanted into infertile animals, which created sperm with the DNA fingerprint of the donor to allow easy tracking of their origin. In lab tests, sperm from transplant recipients successfully fertilized 81 eggs, leading to embryos that developed to the morula and blastocyst stages, which are the stages that normally precede implantation in the mother's uterus. Donor parentage was confirmed in seven of the embryos.
An important step toward human translation
According to senior study author Kyle Orwig of the University of Pittsburgh and Magee-Womens Research Institute, this is the first study to demonstrate that transplanted spermatogonial stem cells can produce functional sperm in higher primates. It demonstrates that spermatogonial stem cells from higher primates can be frozen and thawed without losing their activity, and that they can be transplanted to produce functional sperm that are able to fertilize eggs and give rise to early embryos.
As noted in the accompanying In Translation article by Pierre Fouchet and colleagues, this work "constitutes a milestone in the field of reproduction, and generates hope for restoring fertility in survivors of childhood cancer."
The findings are encouraging because several centres in the USA and abroad already are banking testicular tissue for boys in anticipation that new stem cell-based therapies will be available in the future to help them achieve pregnancy and have their own biological children.
Many questions remain to be answered, like should we re-introduce the spermatogonial cells as soon as treatment is over, or wait until the patient is considered cured of his disease, or when he is ready to start a family? How do we eliminate the risk of cancer recurrence if we give back untreated cells that might include cancer cells?
Co-authors of the paper include lead author Brian Hermann, and others from the University of Pittsburgh School of Medicine, as well as collaborators from the Oregon National Primate Research Centre, University of California at Davis, ITxM Diagnostics in Pittsburgh, and CaridianBCT.
The project was funded by Magee-Womens Research Institute and Foundation, The Richard King Mellon Foundation, and National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development grants: R01 HD055475, R21 HD061289, U54 HD008610, P01 HD047675 and K99/R00 HD062687.
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