Do GnRH analogs protect against ovarian toxicity of chemotherapy

Premature ovarian failure is a well described complication of adjuvant chemotherapy for breast cancer. For a variety of reasons, including fertility and quality of life concerns, individuals being treated for breast and other cancers may wish to avoid loss of ovarian function. In this issue of breast cancer research and treatment, Sverrisdottir et al. [1] report on a substudy of ovarian function outcomes following adjuvant therapy with and without goserelin coadministration among patients enrolled in the ZIPP (Zoladex in Premenopausal Patients) trial. The precise mechanism for the high sensitivity of ovarian tissue to the effects of chemotherapy is unclear. While chemotherapy preferentially affects dividing cells, only a small fraction of ovarian follicles are developing at any time in the normal premenopausal ovary. It has been hypothesized that chemotherapy induced injury to ovarian tissue may result in a feedback loop in which additional follicles are recruited in response to the initial follicle loss, putting further germ cell tissue at risk for damage [2]. It would follow that if ovarian tissue can be made relatively quiescent during chemotherapy, the risk for permanent loss of ovarian follicles should be reduced. Case series and nonrandomized trials in women with breast cancer and hematologic malignancies have suggested a high rate of preservation of menstrual function following coadministration of GnRH agonists and chemotherapy; however, published randomized data are lacking [3]. Current American society of clinical oncology guidelines discourage this approach to fertility preservation outside of a clinical trial [4]. Sverrisdottir et al. suggest that, in the absence of tamoxifen, goserelin coadministration during adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) provides a protective effect on ovarian function. About 36 month follow-up was available for 94 of 123 premenopausal CMF-treated participants randomized, in a 2 9 2 factorial design, to goserelin or no goserelin and to tamoxifen or no tamoxifen, each for 2 years. Endocrine treatment began concurrently with chemotherapy. Patients receiving endocrine therapy had been off treatment for approximately 1 year at the 36 month follow-up visit. At that time, 36% of participants who had received goserelin without tamoxifen during chemotherapy had resumed menstruation, while only 10% of the remaining three groups combined resumed menses. An important question to ask, however, is why goserelin would have a differing effect on subsequent ovarian function whether or not tamoxifen was given as well. In the absence of ovarian suppression, tamoxifen use in premenopausal women has been associated with an increase in ovarian estrogen production that appears to be secondary to a rise in FSH [5]. This is consistent with tamoxifen’s known ability to induce ovulation. Theoretically, this increase in ovarian activity with tamoxifen could increase gonadal susceptibility to chemotherapy toxicity. Patients receiving tamoxifen during chemotherapy without the GnRH analog, however, did not appear to experience a higher rate of ovarian failure than controls in the study by Sverrisdottir et al. In addition, any ability of tamoxifen to increase ovarian cycling during chemotherapy ought to be prevented through suppression of the hypothalamic-pituitary axis when the GnRH analog is added. It is, therefore, unlikely that the ability of goserelin to preserve ovarian function would be significantly influenced by whether the patient also takes tamoxifen. This is an invited commentary to article doi:10.1007/s10549-009-0313-5.