Gonadotropin-Releasing Hormone Agonists for Prevention of Chemotherapy-Induced Ovarian Damage: Prospective Randomized Study
Badawy A, Elnashar A, El-Ashry M, Shahat M
Fertil Steril. 2009;91:694-697
Although cancer is generally associated with older age, certain types of cancers occur predominantly in children or among young adults. Cancers that are more common among older women, such as breast cancer, occur in young women as well. In the past, definitive cancer treatment often resulted in infertility. More recently, improvements in cancer therapy (less destructive surgical options, more effective chemotherapeutic regimens, more focused radiation therapy) have resulted in an increase in survival rates. These higher survival rates, combined with the new treatment approaches in younger patients, have led to an increased number of young cancer survivors with fertility concerns that need to be addressed.
Chemotherapy primarily destroys rapidly dividing cells, both cancer cells and germ cells. The effects of chemotherapy on the reproductive system depend on dose, duration of treatment, and type of agent, with alkylating agents proving particularly toxic to the gonads. Their effect also appears to depend on the cell cycle; inactive cells seem to be less sensitive. With these effects in mind, it has been hypothesized that if the ovary is brought into a quiet, inactive phase, the follicles/oocytes may better resist the harmful effects of chemotherapy. Studies so far have produced controversial results.[3,4]
Breast cancer is one of the most common cancers affecting women. About one quarter of cases are diagnosed in premenopausal women. Breast cancer that develops at a younger age is more likely to be poorly differentiated and is typically associated with less favorable outcome. Therapy involves surgery and chemotherapy. Those who survive are at high risk for premature ovarian failure. For those whose ovaries fail as a result of the treatment, donor egg use remains the only option for starting a family once the cancer therapy has been completed. Often there is no time for assisted reproductive procedures with elective egg or embryo cryopreservation prior to chemotherapy; hormone use for stimulation is generally not advised as it may adversely affect the patients' prognosis. Ovarian tissue and oocyte cryopreservation are available options but are in the early stages and cannot be routinely recommended. If follicle loss resulting from chemotherapy could be prevented, these patients might have hope for starting a family if their cancer treatment is successful.
Badawy and colleagues evaluated the effects of gonadotropin-releasing hormone (GnRH) analog adjuvant treatment during chemotherapy among premenopausal women undergoing therapy for invasive breast cancer. The study randomly assigned 80 women under the age of 40 with regular cycles and normal ovarian function (as evidenced by normal baseline gonadotropin levels) to either receive depot GnRH agonist or not to receive it during their normal chemotherapy regime of 6 cycles of cyclophosphamide, doxorubicin, and 5-fluorouracil. Baseline characteristics were well balanced (age, body mass index, hormone levels, parity). Patients were followed up for 8 months at the completion of their treatment. Significantly more women started to menstruate (89.6% vs 33.3%) and ovulate (69.2% vs 25.6%) in the GnRH-agonist-treated group than in the control group during the follow-up. Moreover, baseline follicle-stimulating hormone level was lower and estradiol levels were higher in the GnRH-agonist group during the follow-up period. Premature ovarian failure was more common in the control group (66.6% vs 11.4%).
The efficacy of cancer treatment has significantly improved over the years, providing better survival rates for reproductive-age women and making fertility concerns more important. The current study suggests that receiving GnRH-agonist treatment for the duration of chemotherapy may reduce the gonadotoxic effect of chemotherapy. Several explanations are offered for the mechanism. The low gonadotropic stage prevents the follicles from entering the final phase of development, allowing them to stay in a more resistant stage. The hypoestrogenic milieu may reduce the ovarian blood flow and therefore could reduce the amount of chemotherapeutic agent reaching the ovary. GnRH agonist may increase the local production of antiapoptotic factors or could have a different direct ovarian effect. Regardless of its mechanism, it appears that GnRH agonist may have a protective ovarian effect against the gonadotoxic effects of chemotherapy. If these results are confirmed, GnRH may be a good option for women who wish to maintain their fertility.
Medscape Ob/Gyn & Women's Health © 2009 Medscape, LLC