M. D. Anderson Cancer Center
Date: February 13, 2009
Duration: 0 / 07:53
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Here at the M. D. Anderson Cancer Center, a lot of patients are cured of their cancer but display various side effects, either toxicities of the chemotherapy or the radiotherapy, and one side effect that we're concerned about especially with young patients is sterility - being the ability to subsequently have children. This occurs with both men and women. Our research is focused on men who are treated with radiation or chemotherapy. Now throughout the United States, about 3,000 men each year are treated for cancer with potentially sterilizing radiation or chemotherapy regimens. In addition young boys, about the same number of young boys, are treated with radiation and chemotherapy which may result in their sterility when they approach adulthood.
In order to understand the mechanisms, I'd like to review some of the process of spermatogenesis, which is the process of sperm formation in the testicle. The process starts off with spermatogonia, which are stem cells and they both renew themselves to keep the population of these cells steady and going, as well as produce differentiating cells. Now once a cell differentiates, it becomes spermatocytes. They no longer can go back to stem cells but are committed in a fixed time, to differentiate into sperm. And that time is between 1 or 2 months, depending on the species. The cells will then go on to become spermatids, or sperm, and if they're unable to do so in a fixed time, these cells will die and there will be no later stage cells. Now for purposes later in the presentation, I'd like to show what happens if the male hormone testosterone is suppressed in normal mammals. ^m00:02:08 The spermatogonia are pretty much unaffected by the lack of this hormone, and at least in many species they'll produce spermatocytes but these spermatocytes are then unable to go on and produce spermatids and sperm. So testosterone is required for these later stages of maturation. Now to get back to the issue that we're concerned with, which is the effects of radiation or chemotherapy on these cells in this developmental process to produce sperm in the testicle. High doses of radiation and chemotherapy could kill all of these stem spermatogonia, in which case there are no cells left to replenish the testis. And methods are needed to try to restore these stem cells. A technique was developed by Dr. Brinster at the University of Pennsylvania in the 1990's where he took testicular cells from a normal mouse, or a mouse with normal spermatogenesis but it was marked with a tran-Z so they could identify the donor cells, injected into the testis of another mouse - the one that was lacking these stem sperm cells - and these transplanted stem cells then restored spermatogenesis and in fact restored fertility in this otherwise sterile mouse. Now this technique has been used in mouse, and in rat, and in fact other animal species and has potential clinical application to cancer patients. And the idea is to take cells from the young boy who has lots of sperm stem cells, but is not producing sperm, so can’t be a candidate for sperm banking like adult men can, take these sperm stem cells, store them frozen, which is possible to store cells at that stage indefinitely, and then after he's treated and possibly rendered sterile, inject those cells back into his testicle and now try to develop techniques to restore spermatogenesis from those cells. Now this whole process hasn't yet been demonstrated in human, but we and others are working on methods to enhance this process.
Now very often when cancer therapy is given, it's not too high a dose and then maybe a few stem cells remain in the testis. In this situation what we've observed in rats, even though those stem cells are present, they don't go on to differentiate to become spermatocytes. So we try different things to see if we could induce them to become spermatocytes, and very surprisingly because we knew that testosterone is required for the later stages of spermatogenesis, but we found that it actually was inhibiting this process. So when we suppressed testosterone, we now got plenty of spermatocytes in these irradiated or chemotherapy treated rats. So that indicates it's testosterone that's inhibiting this process. Well from a practical point of view, if we suppress testosterone we'll get spermatocytes because testosterone is required for the spermatocytes to go on and produce sperm. So what we did was we suppressed testosterone for a period of time, got the spermatocytes, then restored testosterone and let these cells go on to produce sperm and the rats were fertile, at least for a period of several months. We've done the same procedure with mice and it worked essentially the same way. We've tried it with monkeys and others have tried clinical trials in humans, and it doesn't seem to... simple hormonal suppression and restoration does not restore spermatogenesis. So what we're trying to do now is to really understand how this is working in rats, and if we can get these spermatogonia to go to spermatocyte, perhaps by hitting the real target and not having to suppress testosterone, we could get spermatocytes being produced and then they would go on to produce sperm. And these methods might be applicable to help the men who are being treated with cancer therapy. I also want to point out that if all stem cells are killed and spermatogonia have to be transplanted back into the testis, this temporary hormonal suppression also improves the development of the transplanted cells. So this might be applicable to the boys who have stem spermatogonia stored and have the potential of having them transplanted back into the testis. So in this way, which I think is a long term goal, we're trying to restore, preserve or restore, the fertility in many of these patients who are undergoing cancer treatment.
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