The Promise of Oncofertility

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A healthy ovarian follicle matured in the Alginate system, photographed using an inverted microscope and specialty software

More people than ever before are surviving cancer due to modern breakthroughs in medical science. From 1991 to 2004 cancer death rates decreased by more than 13%. Among children, for whom cancer is the second leading cause of death, mortality rates have decreased by nearly 50% since 1975. As these cancer survivors return to the normal course of their lives, many will want to become first-time parents or have additional biological children. However, the more aggressive forms of treatment that have made survival possible, such as chemotherapy and radiation therapies, can also compromise an individual’s ability to later conceive. Fortunately, there are steps patients can take in order to help safeguard their fertility. Men and adolescent boys have long had the option of sperm banking before undergoing fertility-threatening cancer treatment, as done by Lance Armstrong when diagnosed with late-stage testicular cancer. After his bout with cancer, Armstrong went on to win seven Tour de France titles and father three children.

But what options do women have? While more women today are having biological children after cancer, they are still much less likely to do so than male survivors. In part, this is because women have had far less effective and more cumbersome options available to preserve their fertility. Shielding the pelvis during radiation therapy, which can help limit damage to the ovaries, is one common practice, but this method is not foolproof or applicable for all patients. Emergency in vitro fertilization (IVF) is the most common option, whereby a woman’s eggs are harvested, fertilized in vitro, or in a lab, and matured. The resulting fertilized eggs, or embryos, are then frozen until the woman is ready to have a child. It is considered “emergency” IVF because of the urgent timeframe in which the woman’s eggs must be harvested before she undergoes cancer treatment.

What is in vitro fertilization?

Although this option has been fairly effective, it can only be performed on those who are at least eighteen years old and have reached puberty. It also requires hormonal treatments to mature a woman’s eggs for harvesting and fertilization, which causes significant delays in cancer treatments—3 to 4 weeks at a minimum. In addition, these hormonal treatments may not be advisable for those with some forms of cancer, such as hormonal-sensitive breast cancers. Finally, since IVF requires immediate fertilization, it may not be an option for women who do not have a viable sperm partner or do not want to use donor sperm. Although emergency IVF is a positive experience for many, it requires a woman to decide during a very emotional time who should be the biological father of her children—children who may not be born until many years later.

There have also been some clinical trials involving egg freezing, which alleviates the need for immediate fertilization. However, this procedure again involves hormonal treatments, causes significant delays in cancer treatment, and is limited to those who have reached puberty. Also, the pregnancy rates for this option have been very low, making it less promising for those facing a cancer diagnosis.

Faculty at Northwestern began to wonder if an ovary, rather than an egg, could be frozen. The concept was that, prior to fertility-impacting cancer treatment, women and girls could have an ovary removed and cryopreserved, or frozen. Later, when the woman wished to have a baby, a portion of the ovarian tissue could be thawed and an ovarian follicle (an ovum and its support cells) could be matured and fertilized in a laboratory. The resulting embryo would then be carried to term in vivo, or within the woman’s uterus. If the woman is no longer able to carry a child, the embryo could also be placed in a surrogate mother.

This procedure would be a breakthrough in preserving the fertility of women diagnosed with cancer for many reasons. The surgical procedure to remove an ovary does not cause a significant delay in cancer treatment beyond a one or two day recovery, nor does it require the hormonal treatment that IVF does to facilitate egg harvesting. This option is also not limited to those who have reached puberty. A woman is born with her lifetime supply of eggs in an immature state, so girls as young as one year of age could be eligible. Finally, since this procedure does not require immediate fertilization, it allows women more control over not only when to have biological children, but with whom as well.

Many aspects of this procedure are already well-established practices. For example, the cryopreservation and thawing of certain tissue is common, and sperm cryopreservation has high success rates for conception. Also, implanting embryos into a woman who wishes to carry a child is also an established technique—IVF has been successfully used since the late 1970s. But what is missing for this idea to work is how to mature a preserved immature ovarian follicle in vitro in order to prepare it for fertilization. Our lab is currently studying this maturation process.

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One fundamental hurdle Northwestern scientists have already overcome is how to maintain the structure of the ovarian follicle in vitro so it will grow in a natural way, as if it were still intact within the ovary. The ovarian follicle is a unique structure that contains the egg surrounded by and intimately connected to its supporting cells. When placed in the traditional two-dimensional tissue culture dish, such as a Petri dish, the follicle spreads out and the egg fails to grow and mature properly. We determined that the two-dimensional surface of the Petri dish inhibited growth because it disrupted the intimate connections between the ovarian follicle and its supporting cells

To overcome this spreading, we have pioneered a three-dimensional system that supports follicle development, largely, we believe, because the links between the egg and its surrounding cells are maintained, thus preserving the original three-dimensional architecture. The three-dimensional structure is formed by creating an alginate bead around the individual ovarian follicle. Alginate, a gelatinous substance extracted from the walls of some types of algae, is commonly used as a thickener for soups, jellies, and ice cream. We believe that alginate is the best substance to use because it is firm enough to preserve the 3D structure of the egg, but it also has enough give to allow the egg to grow and mature naturally.

Using this three-dimensional environment, we have been able to mature mouse ovarian follicles in vitro to the point they can be fertilized using traditional IVF techniques. These fertilized embryos have resulted in several live and healthy births. Northwestern scientists are applying this breakthrough technique to animal species whose reproductive systems more closely resemble a human’s, and our goal is to mature human ovarian tissue in the laboratory within the next five years.

But the science is only one part of the problem—patient and physician education are other hurdles to overcome. Many patients are not aware that their fertility may be at risk due to cancer treatment, and, since the overriding need at the time of diagnosis is to battle the cancer itself, fertility discussions are often not part of routine cancer care. Patients who aware of the risks and their healthcare providers may not know of emerging options. In fact, despite its relative ease and effectiveness, most male cancer patients do not bank sperm.

Therefore, in addition to basic scientific research, it is important to study the psycho-social side of fertility impairment and how cancer patients make treatment decisions. Working in collaborative efforts with biomedical researchers, a team of social scientists at Northwestern and their colleagues at the University of California San Diego are studying what cancer patients know about their own fertility, the possible risks associated with treatment, if/how they discuss these issues with their healthcare team, and how they ultimately decide whether to go ahead with a fertility preservation procedure. This area of research will also identify if certain groups, such as minority groups or younger patients, are missing the message during their initial diagnosis and consultations with their cancer-care team. Hopefully this body of research will help train physicians on how to best approach and integrate the issue of fertility into routine cancer care, as well as educate the public about the importance of considering fertility during a cancer diagnosis.

Northwestern scientists have termed this new field oncofertility—a broad scope approach to studying the intersection of cancer and fertility. However, the techniques of ovarian cryopreservation and in vitro maturation will have applications to a host of women aside from cancer patients. For example, women diagnosed with many autoimmune diseases such as lupus, scleroderma, and rheumatoid arthritis have an increased chance of infertility from the drugs, such as Cyclophosphamide, used to treat their disorders. There might also be applications for women in the military whose fertility may be at risk due to the stress of warfare or exposure to chemical agents. All patients should be able to preserve their fertility in the face of a threatening condition, and we hope to provide them with the knowledge and options to do so.

 

ASK THE EXPERT:

Q: The article mentions that one reason freezing ovarian tissue is necessary and so promising is because freezing individual eggs has not been very successful. Why is this? Shouldn't it be as straightforward as freezing sperm?

The egg is the largest cell of the body and contains water, proteins, DNA, and many other substances necessary for the early stages of development after fertilization. Because eggs contain water, ice crystals form during freezing, which can fracture and destroy its delicate structure. This leads to several conditions that impair fertilization and embryo quality. (read more)

Q: At some point, one must make the leap from testing the egg maturation process in animals to testing in humans. What are the scientific and social issues involved?

From a scientific standpoint, studies in the rhesus monkey model will be essential for optimizing the in vitro follicle maturation system that will eventually be translated to women. Much of our work to date was performed in the mouse animal model, however non-human primates, such as the rhesus monkey, better mimics the structure and physiology of humans. (read more)

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