Ovarian Suppression for Prevention of Premature Menopause and Infertility: Empty Promise or Effective Therapy?

Fertility and premature menopause are major concerns for young patients who are undergoing treatment for cancer. Young women with breast cancer face particular challenges when considering future fertility compared with other young cancer survivors. The greatest concern is whether preservation of ovarian function and a subsequent pregnancy in a breast cancer survivor could increase the risk of recurrence, particularly in patients with hormone receptor– positive disease. Although there have been a number of observational studies that have suggested no detriment from having a pregnancy after breast cancer, concerns remain for many women and their providers. Even if a woman does not go on to become pregnant, continued menstrual cycling, an imperfect surrogate measure for ovarian function and fertility, has been associated with decreased survival in women with hormone-sensitive disease. Whether suppressing ovarian function in women who remain premenopausal after chemotherapy reduces risk in the era of tamoxifen is the subject of ongoing study, notably the Suppression of Ovarian Function with Triptorelin (SOFT) trial; it has closed to accrual and we await its results. Importantly, for women who are interested in a future biologic child, breast cancer chemotherapy can diminish a woman’s fertility even if she does not experience immediate menopause. In addition, standard hormonal therapy with tamoxifen for women with hormone-sensitive disease entails 5 years of treatment during which a pregnancy is contraindicated and a woman’s ovaries are aging, with an associated decline in fertility. Finally, it can be difficult to determine whether a survivor of breast cancer is fertile. A woman who is menstruating may be infertile, and women who are amenorrheic, especially women who are receiving tamoxifen, which can affect menstrual cycling, may remain fertile. Nevertheless, for young breast cancer survivors who are interested future fertility, as well as those who are concerned about the potential effects of premature menopause on quality of life, sexual functioning, and bone and cardiovascular health, there has been great interest in trying to maintain ovarian functioning after breast cancer chemotherapy. Reported rates of chemotherapy-related amenorrhea and premature menopause range from 10% to 90% depending on age and treatment regimen studied, definition of amenorrhea or menopause, and length and method of follow-up. Several uncontrolled studies have suggested decreased incidence of amenorrhea with the use of gonadotrophin-releasing hormone (GnRH) agonists throughout chemotherapy, compared with historical controls. The use of these agents is appealing, given that they are readily available and are generally less cumbersome than available alternative strategies including in vitro fertilization and embryo cryopreservation before treatment. However, available data from both human and animal studies have been mixed, and reproductive biologists have questioned the biologic plausibility of the preservation of fertility by GnRH agonists, arguing that randomized controlled trials are needed to evaluate efficacy. In the article that accompanies this editorial, Munster et al present one such trial. In their study, premenopausal women age 44 years and younger were randomly assigned to receive triptorelin or no triptorelin during adjuvant or neoadjuvant modern breast cancer chemotherapy. In contrast to previous studies, women were stratified by age, estrogen receptor status, hormonal therapy use, and chemotherapy regimen. The main outcome measures were resumption of menses and levels of follicle-stimulating hormone (FSH), inhibin A, and inhibin B. The study was stopped early for futility after 49 patients (of a planned 124) had been enrolled. Menses resumed in 90% of the women in the control group and 88% of women in the triptorelin group (P .36). There was also no difference in the time to return of menses between the two groups (median of 5.8 months in the triptorelin group and median of 5.0 months in the control group; P .58). Two patients were reported to have had spontaneous pregnancies in follow-up, both of whom were in the control group, although follow-up was relatively short for this outcome. The measurement of markers of ovarian reserve, including FSH, inhibin A, and inhibin B, measured at baseline and serially in follow-up, seemed to show diminished fertility in both groups over time, consistent with the menopausal status of these patients. This study provides important information for our evolving understanding of the potential role of ovarian suppression in women with breast cancer. The investigators used rigorous definitions of continued or resumption of menses, and there was a median follow-up of 18 months. Importantly, they accounted for age mix and chemotherapy regimen as well as the use of tamoxifen in their analysis. Tamoxifen does not seem to have a detrimental JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 30 NUMBER 5 FEBRUARY 1