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Yale-New Haven Hospital, New Haven, Connecticut, USA HealthLINK: Women's Health
February 14, 2000

News this month
Doctors restore ovarian function

In September 1999, Dr. Kutluk Oktay reported at the joint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society on the first successful attempt to restore a woman's ovarian function by reimplanting previously frozen ovarian tissue.

…the first successful attempt to restore a woman's ovarian function by reimplanting previously frozen ovarian tissue.

Surgeons, led by Dr. Oktay of New York Methodist Hospital, implanted a portion of an ovary into a 29-year-old Arizona woman. She had had the organ, her only ovary, removed and frozen one year earlier before receiving treatment for an obstetrical ailment. Doctors used laparoscopic instruments to implant the tissue through three tiny holes in the patient's pelvis.

Within three weeks of the surgery, the surgeons detected signs of blood flow to the reimplanted organ. After three months, the woman, who had had the other ovary removed when she was 17, had signs of ovulation after treatment with artificial hormones. The woman developed an egg, ovulated, and had a normal menstrual period, according to Dr. Oktay.

Researchers intend the procedure only for cancer victims or other patients who want children after undergoing treatments that would destroy their reproductive function.

While initial media reports trumpeted the ovary transplant as a menopause cure, the researchers emphasize they intend the procedure only for cancer victims or other patients who want children after undergoing treatments that would destroy their reproductive function.

Not a cure for menopause
Dr. Oktay told the audience at the fertility conference he can't help the hundreds of menopausal women who have been calling him, seeking to turn back biological clocks, since his breakthrough work was reported. "This is not a menopause reversal procedure."

Dr. Oktay conceded that 29-year-old dancer Margaret Lloyd-Hart was not the ideal candidate for the procedure; she wanted it not to restore fertility but to feel and perform better than she could on hormone replacement therapy alone. Lloyd-Hart flew with her frozen ovary from Tucson to New York to have the engraftment.

Dr. Oktay and colleagues thawed out one piece, cultured it and found that the tissue had viable follicles and was steadily producing increasing amounts of estrogen, progesterone and testosterone. "But there was 50 percent damage to tissue, as is to be expected with cryopreservation," he said. Dr Oktay, who is chief of reproductive endocrinology and infertility in the department of obstetrics and gynecology at New York Methodist, rebuilt her ovary from 80 sections stored in 60 cryo-preservation vials.

"The ideal candidate remains the young woman who has cancer."

"The procedure needs to be done before age 32 because after that the ovaries do not have enough eggs to compensate for all the loss from freezing, thawing and transfer. The ideal candidate remains the young woman who has cancer.

"Freezing sperm has long been an option for men undergoing cancer therapy, but it became an option for female patients only when basic studies showed that eggs are better preserved in ovarian tissue than frozen individually." Since mature eggs have a high water content, they suffer a kind of freezer burn.

The ovarian graft procedure was developed by English biologist Roger Gosden, who praised Dr. Oktay and his New York team for their demonstration of proof of principle and their successful reconstruction of the sectioned ovary. "Before this was done, we couldn't be sure it would work and we thought the reconstruction would be the biggest problem," Dr. Gosden said.

"This case indicates that we are on the cusp of safe, reliable transplantation of human ovarian tissue," said Larry Lipshultz, president of the American Society for Reproductive Medicine.



The Yale Onco-Fertility Center

If you have been diagnosed with cancer or another medical condition that threatens your fertility, you may wish to find out more about your options. At Yale-New Haven Hospital, the Yale Onco-Fertility Center is a multidisciplinary group of physicians focused on fertility issues in cancer patients. They are freezing and storing ovarian tissue for women who meet the medical criteria, as well as actively researching modifications of the freezing technique to increase the survival rate of the ovarian tissue. The center's program also provides psychological support for couples facing fertility issues related to cancer and other options to preserve fertility. Call (203) 785-5951 to learn more.


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Steven Palter, M.D.

Freezing ovarian tissue offers options for some women

Dr. Oktay's work is a very important step in the evolution of our efforts to make it possible to perform ovarian transplants successfully in women. During the last 10 years, investigators have been successfully working on freezing ovarian tissue and reimplanting it in mice. Not only have they been able to get the ovaries to function, the mice have been able to reproduce.

Dr. Roger Gosden, a professor at Leeds University in England, took the technique one step closer to women by successfully grafting ovarian tissue in sheep, whose ovaries are structurally much more similar to humans. All of this work was done using modifications of the protocols developed for freezing sperm and embryos for the past 15 years.

"We have been studying freezing techniques for ovarian tissue for women who face a high probability of losing their fertility either because of treatment for cancer or for other conditions that threaten the fertility of young women."

We have been studying freezing techniques for ovarian tissue for women who face a high probability of losing their fertility either because of treatment for cancer or for other conditions that threaten the fertility of young women. Dr. Oktay's surgery is the first case of reimplantation of tissue that has been frozen. It showed that frozen ovarian tissue could function after being reimplanted in a patient. The woman did have to take large quantities of fertility medications, and it's unclear how long the tissue will continue to function.

Dr. Gosden's group has shown us about 50 percent of frozen ovarian tissue could survive the freeze/thaw process, but it's likely that those that do survive would not remain viable for very long after reimplantation.

"It's quite possible within the next five years we will be able to have good function from reimplanted tissue."

The time for freezing is here; transplants may be premature. So, does it make sense at this point to subject a woman to the risk and expense of surgery if our chances of success are very small indeed? We believe that if a woman is facing a very high probability of losing fertility because of some medical condition, freezing ovarian tissue is something she and her partner should consider. We have learned a lot about improving the conditions for freezing and storing ovarian tissue, and it's quite possible within the next five years we will be able to have good function from reimplanted tissue.

We have two goals:

  • preserving natural hormonal activity for women who lose their ovarian function premenopausally, and
  • the potential to enable these women to maintain fertility and have children.

We don't know yet if either of these goals is possible, but research suggests it is, and we believe we're very close to finding the answer. I would not consider the procedure for a 35-year-old woman who is interested in delaying childbirth for 10 years for lifestyle reasons.

However, if a 25-year-old woman with breast cancer or Hodgkin's disease was scheduled for treatment, but wanted to preserve her potential to have children, I would. These women have no other option, so freezing ovarian tissue is a valuable alternative for them. If a woman undergoes chemotherapy or radiation for malignancies during her reproductive years, she has between a 40 and 80 percent chance of losing her fertility depending on her age and the type and quantity of chemotherapy or radiation therapy.

The surgery
The surgical procedure to remove ovarian tissue is very safe, but it is still an operation with costs and risks. The surgery is usually performed laparoscopically under general anesthesia, but a new technique is being used that requires only a local anesthetic, lowering both risk and expense. However, the less invasive procedure yields a small fraction of the tissue that can be removed under general anesthesia.

"Tissue can be frozen for five years or more, unthawed and reimplanted surgically."

How does it work? A surgeon may remove a whole ovary or a piece of ovary. The tissue is then cut into small pieces, which survive the freezing process better than large pieces. The tissue is frozen and stored in liquid nitrogen at -196 degrees Centigrade. The tissue can be frozen for five years or more, unthawed and reimplanted surgically either in the abdomen or under the skin of the forearm. The abdominal site is closer to the normal site of action, but an arm is an easier site for implantation and monitoring. We don't know yet which is better. Another possibility is to grow the tissue outside of the body in a dish once thawed.

All research indicates good survival of the ovarian tissue. What remains to be proven is if we can restore fertility. Investigators around the world are working on this.


Dr. Palter is an attending obstetrician/gynecologist at Yale-New Haven Hospital and assistant professor and clinic chief of reproductive endocrinology and infertility at Yale University School of Medicine.


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