Hormone-blocking agent preserves fertility in women undergoing chemotherapy

HAIFA, Israel and NEW YORK, NY, February 28, 2001 -- The toxicity of cancer chemotherapy agents often leaves women of childbearing age permanently infertile. A new hormone-blocking procedure, in which a patient's reproductive system is placed into a type of temporary "prepubescent stasis," enables women to have children after chemotherapy ends.

"Our research stems from the observation that pre-pubescent girls who undergo chemotherapy fare much better in terms of preserving their fertility than 25- or 35-year-old women," explains Dr. Zeev Blumenfeld, a researcher of reproductive endocrinology at the Technion-Israel Institute of Technology who headed the study.

Dr. Blumenfeld and his colleagues discovered that they could simulate the "pre-pubertal hormonal milieu" and protect the ovarian function of young women by administering a natural hormone called gonadotropin-releasing hormone analogue [GnRH-a]. The agent is given to patients beginning two weeks before they start chemotherapy and for about 4 to 6 months or until completion of chemotherapy. Gonadotropins are hormones responsible for the activity of both the ovaries and testes, and GnRH-a blocks the release of these hormones, creating a state in which the hormonal activity of the pituitary gland and ovaries is halted and a woman's reproductive system is temporarily shut down.

"Our results suggests the beneficial effect of GnRH-a co-treatment may be extrapolated toward the preservation of future fertility and ovarian function in every young woman in the reproductive age exposed to chemotherapy agents," says Dr. Blumenfeld.

According to Dr. Frederick Naftolin, chairman of the Department of Obstetrics and Gynecology at Yale University, Dr. Blumenfeld's research is another achievement in a chain of advances by Technion fertility researchers at Rambam Medical Center in Haifa, Israel.

"The Technion medical faculty has a long and distinguished history of assisting its patients to become pregnant," Dr. Naftolin says. "Dr. Blumenfeld has performed an interesting study on the possible use of a hormone agonist (GnRH-a) in an attempt to forestall damaging effects of chemotherapy on the ovary. It is safe to say that the Technion will continue to lead the field in this important area of women's healthcare."

Dr. Blumenfeld’s findings, which appear in the January/February issue of the Journal of the Society for Gynecologic Investigation (Volume 8, 2001), were presented earlier this month in Geneva, Switzerland, at the Sixth International Symposium on GnRH Analogues in Cancer and Human Reproduction.

Premature ovarian failure, or POF, is a common long-term consequence of the toxic effects of chemotherapeutic agents. While such damage is reversible in other tissue made up of rapidly dividing cells, such as bone marrow, the number of potential fetal egg cells is fixed before a woman is even born.

Dr. Blumenfeld began researching women receiving cyclophosphamide, one of the most widely used cancer chemotherapy agents, also used in patients with lupus nephritis, a severe degenerative disease of the connective tissue. Premature ovarian failure has been reported in as many as 100 percent of women over age 30 who receive cyclophosphamide treatment, in 50 percent among patients between the ages of 20-30, and in 13 percent of those under age 20. A monthly injection of

GnRH-a for six months preserved ovarian function in all the women. Each monthly injection costs $300 to $400. The same medication is routinely used worldwide for in vitro fertilization (IVF) to prevent premature ovulation.

In 1991, Dr. Blumenfeld began exploring the protective effects of GnRH-a, an artificial analogue of a natural hormone, to see if it could benefit women receiving toxic chemotherapy. He reasoned that the same protection against ovarian chemotoxicity reported in women receiving cyclophosphamide for lupus nephritis might also prove true in women being treated for cancer.

Today, Dr. Blumenfeld has tested monthly GnRH-a injections in more than 100 women aged 15 to 40 who have received chemotherapy with or without radiation treatment for Hodgkin’s disease or non-Hodgkin’s lymphoma.

Among women treated with GnRH-a, 95 percent regained normal cyclic ovarian function after chemotherapy ended. Among women who did not qualify for co-treatment with GnRH-a, 55 percent experienced premature and irreversible menopause.

"The female fetus is born with a set number of primordial follicles that contain immature eggs," Dr. Blumenfeld explains. "At 20 weeks, a female fetus has around seven million of these immature eggs. At birth the number has already fallen to 3 to 4 million -- and this number declines steadily as a woman ages. By the time she enters puberty, she has between 300,000 and 400,000 eggs, and at menopause this number falls to fewer than 1,000."

Dr. Blumenfeld and other experts are optimistic that co-treatment with the gonadotropin agonist analogue will soon become a standard part of chemotherapy treatment for women of childbearing age.

"I believe the procedure will become almost mandatory in every young woman receiving chemotherapy," he says. "As the survival rates of young female cancer patients continues to improve, protection against infertility caused by chemotherapy, with or without radiation treatment, becomes a high priority."

The Technion-Israel Institute of Technology is Israel's leading scientific and technological center for applied research and education. It commands a worldwide reputation for its pioneering work in computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine. The majority of the founders and managers of Israel’s high-tech companies are Technion graduates. The Technion’s 19 faculties and 30 research centers and institutes in Haifa are home to 13,000 students and 700 faculty members.