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New methods to preserve fertility

Preserving fertility

Where once physicians’ only concern was saving lives, new techniques under study at Yale can also preserve fertility in women undergoing treatment for cancer.

by Jennifer Kaylin
Photographs by Terry Dagradi

A new method for preserving oocytes requires bathing them in a protective solution, then slow-cooling them with liquid nitrogen. This procedure has more than doubled the success rate to between five and six babies per 100 eggs.

For more than two years Tracy Urbano endured menstrual periods that were alarmingly intense. She suffered heavy bleeding that might last as long as six months straight. Once she fainted and had to be taken to the hospital because she’d lost so much blood.

Her doctor tried to regulate her periods with birth control pills. When that approach failed, he ordered an ultrasound, which revealed that the lining of her uterus was unusually thick. Through a sonohysterogram, a procedure to check for abnormalities of the uterine cavity that could interfere with pregnancy, Urbano’s doctor discovered numerous polyps—benign growths that are usually easily removed with dilation and curettage. But when he began the procedure, he made a distressing discovery: endometrial cancer had spread throughout her uterus.

Urbano needed to have a complete hysterectomy as quickly as possible. The diagnosis was devastating to the 27-year-old Northford, Conn., woman, but equally upsetting was the realization that the surgery would leave her unable to have children. “I grew up in a big Italian family,” says Urbano. “Ever since I was a little girl, I’d always dreamed of being a mother, but they told me there was nothing they could do.”

A conversation among colleagues brings hope
Shortly after Urbano’s diagnosis, her doctor, Peter E. Schwartz, M.D., HS ’70, the John Slade Ely Professor of Obstetrics, Gynecology and Reproductive Sciences, ran into a colleague in the department, Pasquale Patrizio, M.D., M.B.E., professor of obstetrics, gynecology and reproductive sciences, described his patient’s predicament. Patrizio, the director of the Yale Fertility Center and the OncoFertility program, had recently begun using a new egg-freezing technique known as slow oocyte cryopreservation to enhance women’s fertility options. He thought he might be able to help Urbano.

Patrizio is one of several doctors at Yale in a variety of specialties who are working on solutions for patients whose cancer treatments could compromise their fertility. From oocyte preservation to radical vaginal trachelectomies (excision of the cervix and surrounding parametria without removing the uterus) for some cervical cancers to progestin treatment in early-stage endometrial cancers, innovative methods for fertility preservation are being explored and refined at Yale in response to growing patient demand. Patrizio has recently received a grant from the pharmaceutical company Serono to study with Dagan Wells, Ph.D., an assistant professor in the department, changes in gene expression of eggs during the freezing/thawing process in order to recognize—at the molecular level—and avoid potential cryotoxic events.

In the past two decades, the rate of cancer survival in the United States has improved dramatically. Earlier detection coupled with improved treatment options has increased survival rates for all cancers. According to the National Cancer Institute (NCI), for females under 45 (an age near the end of the childbearing years for most women) the survival rate rose from 72.8 percent in the late 1970s to 81 percent in the late 1990s. For men, the survival rate increased from 59.8 percent to 69.8 percent during the same period.

With many women deferring childbearing until their mid-30s and beyond, oncologists are treating a growing number of women for whom fertility remains a major priority. In the past these patients would have had to choose between survival and fertility, but new surgical techniques and hormonal treatments have made it possible for an increasing number of cancer survivors to have children.

“It’s an elegant commentary on where we stand with respect to cancer treatment,” says Charles J. Lockwood, M.D., the Anita O’Keefe Young Professor of Women’s Health and chief of obstetrics and gynecology at Yale-New Haven Hospital. “The focus used to be on survival. … We can now focus on quality of life.”

“Ten years ago, the term fertility preservation didn’t exist,” says Kutluk Oktay, M.D., director of the Fertility Preservation Program at the Weill Medical College of Cornell University in New York City and president of the Fertility Preservation Special Interest Group of the American Society of Reproductive Medicine. “Now, we’re slowly seeing these procedures becoming a standard part of care.”

In Urbano’s case, Patrizio recommended that she consider freezing both embryos and unfertilized eggs. During a four-hour consultation and evaluation with Patrizio’s staff, Urbano learned how to inject herself with fertility drugs. These medications contain hormones that increase a woman’s natural egg production from just one ovum per cycle to as many as 15. Every other day Urbano went to Patrizio’s office for an ultrasound to track the growth of the egg follicles. The procedure took about three weeks, forcing Urbano to postpone her surgery by a week.

“My doctor was a little concerned (about the delay), but I really wanted this done,” recalls Urbano, who is single. “I couldn’t have dealt with the surgery aspect if I thought I couldn’t have children.”

Patrizio harvested 16 eggs. Six weren’t mature enough to work with, but six others were fertilized with the sperm of an anonymous donor and frozen as embryos. The other four ova were frozen using the new method of oocyte cryopreservation. “It was just the biggest blow, being told I wouldn’t be able to have my own children,” Urbano says. “Now that’s not a concern. It’s just made everything a little bit easier for me.”

Understanding at the molecular level
Oocyte freezing is just one of many clinical innovations and research initiatives being explored and fine-tuned by medical school faculty.

“We can’t preserve fertility in every woman, but we now have things to offer them,” says Emre U. Seli, M.D., assistant professor of obstetrics, gynecology and reproductive sciences. Seli is a member of the gamete biology core, a group of six Yale researchers from different backgrounds who work together to develop innovative therapeutic options for women with reproductive problems. One team member, Joshua Johnson, Ph.D., an assistant professor in the department, recently reported the generation of eggs from bone marrow stem cells in a mouse model. This controversial discovery challenges the long-held belief that female mammals are born with a finite number of eggs and opens up new possibilities for the development of treatments for infertility.

Seli says that reproductive therapies have traditionally been developed with very little understanding of what was occurring on the molecular level. “Our group’s main interest,” he says, “is using cutting-edge scientific techniques to understand the development of the egg and embryo and what can go wrong, so we can offer all available techniques in an evidence-based manner.”

About 120,000 people in the United States under the age of 45 are diagnosed with cancer annually, the NCI reports. It is often difficult for oncologists to guide patients who wish to preserve their fertility. According to Seli, oncologists are not always aware of the available options and there is no well-structured referral system between clinicians and researchers.

Sperm and embryo cryopreservation are the fertility preservation techniques most familiar to the public. They are now widely available and considered standard practice. Other methods show promise but are considered investigational. Oocyte cryopreservation is among the most promising of the new methods. The American Society of Reproductive Medicine classifies it as an experimental procedure, but last December the School of Medicine’s institutional review board approved use of the technique. Patrizio says that his office has already handled 10 cases, including three in which the patients had cancer.

“One of my goals is to put Yale on the map as a premier fertility preservation center. That’s why we’re putting together this program,” says Patrizio.

Although variations of the cryopreservation technique have been tried for 15 years, damage to the eggs by freezing resulted in a disappointing track record of only about two babies for every 100 eggs frozen. The new method—bathing eggs in protective solutions, slow-cooling them with liquid nitrogen and thawing them—has doubled the success rate to five or six babies per 100 eggs. The procedure’s success is also dependent on the age of the patient. Harvesting eggs when the woman is under 35 increases the odds of a future successful pregnancy.

A ban leads to a new technique
The latest freezing method was developed by Veronica Bianchi, Ph.D., and Andrea Borini, M.D., at Tecnobios Procreazione, a private fertility clinic in Bologna, Italy, in response to a 2004 Italian law that bans the freezing of human embryos. Egg preservation is allowed because the eggs are unfertilized. Bianchi is now working with Patrizio at Yale to further refine the methods and improve the success rate. This technique is appealing to women who don’t have a partner and don’t want to use sperm from an anonymous donor. Patients who have ethical objections to embryo freezing also find oocyte preservation an acceptable alternative. “You don’t have frozen embryos—just eggs, so you have a lower ethical barrier to leap,” says Lockwood.

Fertility preservation almost always centers on women, whose reproductive biology is far more complex than men’s. “Sperm is easy. It can be readily stored in high volumes and frozen with minimal preparation. Men in their 80s produce perfectly good sperm,” says Lockwood. “The big issue is the egg.”

As the field of fertility preservation advances, oncologists and fertility experts agree that there needs to be more communication and cooperation between disciplines. The American Society of Clinical Psychologists reports that approximately half of oncologists do not initiate fertility discussions with patients at the time of diagnosis.

Dennis L. Cooper, M.D., HS ’82, professor of medicine (medical oncology) and clinical director of the hematopoietic stem cell transplant program, says he understands doctors’ reluctance to address fertility issues. “When we talk to patients, we always tell them there’s a possibility this treatment will knock out their fertility, but I can’t say that I’ve had a single patient who has actually gone through with egg or embryo freezing,” he says. The problem, Cooper says, is that often patients are too sick to delay treatment long enough to go through an egg retrieval cycle. “I’m not trying to be negative, but it places the patient in a very difficult position: Do you delay therapy for the possibility of having kids, when the odds of that procedure being successful are not very good? It puts additional stress on an already stressful situation.”

To provide oncologists with better guidance, a panel convened by the American Society of Clinical Oncology in February 2005 developed the first guidelines to address fertility preservation options for people living with cancer. The guidelines were published in the June 20, 2006, issue of the Journal of Clinical Oncology. Patrizio, who served on the panel as both a bioethicist and a reproductive endocrinologist, says he’s encouraged by the response he’s received from oncologists. “It became obvious to me a few years ago, when I talked with colleagues who treat cancer patients, that we were completely apart.”

“Until now,” says Oktay, the senior author of the guidelines, “there’s been no clear guidance for discussing and initiating fertility preservation with cancer patients.”

Already there are signs that the lines of communication are opening. Jessica Dorey, R.N., coordinator of Yale’s gestational carrier and egg donation program, says that patient referrals from oncologists have gone up in recent years. “Everyone seems to be much more aware of the options,” she says. And now that more cancer patients are seeking Yale’s reproductive services, Yale is trying to expedite the process so they can resume cancer treatment as quickly as possible. “It all happens very quickly, and it can be extremely overwhelming,” Dorey says. “We try to make it as easy for them as possible.”

Around the world, as many as 40,000 women a year who are diagnosed with cancer while they are pregnant choose to continue the pregnancy rather than submit to a treatment that might jeopardize the fetus or their future fertility.

This number doesn’t surprise Lockwood at all. “The drive to reproduce is palpable and common to all animals. It’s the primary drive,” he says. “We see the faces of desperate couples all the time. If you told them they had to climb Mount Everest to have a baby, they’d gladly do it. Those of us who see that kind of longing just really want to help.” YM

Jennifer Kaylin is a contributing editor of Yale Medicine and a freelance writer in New Haven.

New methods to preserve fertility

Besides oocyte cryopreservation, researchers are exploring other methods to preserve female fertility. For women with early-stage cervical cancer, a more conservative, but technically challenging surgery called radical vaginal trachelectomy has been found to preserve fertility in some patients. A recent study found that of 319 women who had the surgery, 147 pregnancies were recorded, including 99 live births (67 percent). Charles J. Lockwood, M.D., the Anita O’Keefe Young Professor of Women’s Health and chief of obstetrics and gynecology at Yale-New Haven Hospital, says this procedure still needs improvement. It is used only for the “absolutely desperate,” because of the high rate of subsequent preterm deliveries associated with it.

Younger patients diagnosed with some borderline ovarian tumors can undergo a more conservative surgery, in which the surgeon removes only the affected ovary, leaving the unaffected ovary and uterus intact. So far, data show that the outcome after this surgery is comparable to that of the more radical approach of removing both ovaries and the uterus.

And patients with early-stage endometrial cancer can opt for progesterone therapy instead of an immediate hysterectomy. After the cancer has been diagnosed, the patient begins hormone therapy, which temporarily suppresses the cancer. The aim is to buy the patient enough time to conceive and carry the pregnancy to term. Once the baby is born, the patient stops taking the hormones and has a hysterectomy.

“This is a reasonable course of action for many early-stage endometrial cancers, but it requires careful monitoring,” says Lockwood. “We’ve cared for three patients using this approach, and they’ve all done fabulously well.”

A woman’s fertility can be compromised by any treatment for cancer that interferes with the functioning of the ovaries, fallopian tubes, uterus or cervix, or that causes a hormonal imbalance. Surgery is the most obvious way in which fertility can be lost, but other causes include the patient’s response to the chemotherapy or radiation, the method of administration (oral or intravenous), the dose intensity and the size and location of the radiation field.

For patients who need pelvic radiation, a surgical technique called ovarian transposition is sometimes used to reposition the ovaries at a safe distance from the radiation field. This approach, which is relatively simple and minimally invasive, is most commonly used in patients with Hodgkin’s disease, cervical and vaginal cancers and pelvic sarcomas.

Other therapies being explored include administration of gonadotropin-releasing hormone. This hormone temporarily puts the body in a menopausal state, which is believed to result in less damage to reproductive organs during chemotherapy. Another technique, still experimental, is ovarian tissue cryopreservation. Ovarian tissue is removed from the cancer patient prior to treatment, and frozen if it is found to be free of metastatic disease. Once the patient is cured and wants to get pregnant, the cryopreserved ovarian tissue is thawed and placed back in the ovary or another body part that is more easily accessible, such as the subcutaneous tissue of the abdomen, and that can accommodate the tissue and allow it to function. It has been shown that ovarian tissue removed prior to the initiation of cancer treatment is functional following the thawing process, but only for a short time. Worldwide, two babies, in Belgium and in Israel, have been born using this option when the ovarian tissue was placed back in the pelvis where the ovary is normally located. This fall Pasquale Patrizio, M.D., M.B.E., professor of obstetrics and gynecology, the director of the Yale Fertility Center and the oncofertility program, is starting a new project to perfect the method of ovarian preservation. Instead of freezing sliced tissue, he plans to freeze the entire ovary, which he believes will better survive the freezing and thawing process.

—J.K.