Gonadotropin-Releasing Hormone Agonists for the Preservation of Ovarian Function During Chemotherapy

Protecting fertility in patients with cancer is becoming a relevant subject, and we would like to make some observationsonthe data presented in the recent article by Munster et al and the accompanying editorial. The study was designed to investigate whether gonadotropin-releasing hormone analogs are able to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. This treatment in the current study did not confer any protection, contrary to what has been published by other groups in recent years. One of the most complex aspects in these studies is the definition of regular menstruation before treatment. The current study required the women to be younger than age 45 years, with at least two cycles in the previous six months and a follicle-stimulating hormone (FSH) level below 40 mIU/mL. This policy is likely to introduce a form of selection, especially in the age group between 39 and 44 years, with a potential reduced ovarian reserve and therefore more prone to develop amenorrhea after (neo) adjuvant chemotherapy. As a result of the young age of patients included in the study, it would have been preferable to enroll only women with regular menstrual activity in the 6 months preceding the start of chemotherapy to avoid an unjustified bias. Analyzing the results of the ZORO (Zoladex Rescue of Ovarian Function) trial that failed to demonstrate a significant protective effect of goserelin on ovarian function in patients with breast cancer treated with neoadjuvant chemotherapy,5 Del Mastro6 observed that "It may be useful to better clarify the definition of regular menses or normal ovarian function.” An additional element of discussion is that it is not specified in Munster’s study in which time of the menstrual cycle plasmatic FSH was determined, and this aspect is not trivial given that the cutoff value used (40 mIU/mL) can be considered normal in the secretory phase, whereas this value is clearly suggestive of potential ovarian failure when observed in the proliferative phase of the cycle. Similarly, it is not clear at what stage of the menstrual cycle determinations of Inhibin A and B were made; this is likely to cause a serious bias, because in perimenopausal women, reduced levels of Inhibin B during the follicular phase (with high levels of FSH and estradiol normal) are suggestive of perimenopausal state with reduced ovarian reserve. We believe that it would be useful to add the determination of anti-Mu¨llerian hormone (AMH) as a predictive marker of the ovarian reserve. AMH declines with age in adult women and also its concentrations are stable during the menstrual cycle (that are interesting), unlike FSH and luteinizing hormone. We believe that AMH determination could be a useful and early predictive marker of ovarian damage from chemotherapy in young patients with breast cancer and this marker should be used extensively in future studies investigating the risk and incidence of chemotherapy-induced amenorrhea in this subset of patients