Questioning GnRH analogs for gonadal protection in cancer patients

Abstract

To the Editor: We read the recent article by Badawy et al. (1Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar) with great interest, but we have concerns about their study's interpretation that gonadotropin-releasing hormone analogs (GnRH-a) preserve fertility. Randomization does not guarantee similarity among groups. The authors did not specify the cycle day on which the hormone levels were drawn, and both E2 and P4 were different between the groups at baseline (the authors stated in the results that E2 was higher in the GnRH-a + chemotherapy group, but their table shows the opposite). It is interesting that both baseline E2 and P4 levels were elevated, indicating that all patients were in the luteal phase, which is improbable if the patients were randomly selected. Thus, lower follicle-stimulating hormone (FSH) levels in the GnRH-a treatment group does not indicate better ovarian reserve because higher E2 levels in that group would have spuriously suppressed the FSH levels. If these levels were drawn on cycle day 2 or 3, then E2 levels >75'pg/mL would have indicated diminished reserve in both groups (2Scott R.T. Toner J.P. Muasher S.J. Oehninger S. Robinson S. Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome.Fertil Steril. 1989; 51: 651-654Abstract Full Text PDF PubMed Scopus (538) Google Scholar). Further, even though the authors stated that ultrasounds were done on “married” patients, the antral follicle counts were not reported. The percentage of patients who were estrogen receptor–positive and used tamoxifen in each group was not mentioned. Tamoxifen is an ovarian stimulant and raises both estrogen and progesterone levels significantly. In long-term use, tamoxifen can also cause ovarian cysts and even amenorrhea in women with normal function (3Shushan A. Peretz T. Mor-Yosef S. Therapeutic approach to ovarian cysts in tamoxifen-treated women with breast cancer.Int J Gynaecol Obstet. 1996; 52: 249-253Abstract Full Text PDF PubMed Scopus (23) Google Scholar). We are also concerned with extremely high incidence of amenorrhea in the control group. Despite the authors' claim, the incidence of amenorrhea after cyclophosphamide-based treatments for women under age 40 has been consistently <30% (4Sonmezer M. Oktay K. Fertility preservation in young women undergoing breast cancer therapy.Oncologist. 2006; 11: 422-434Crossref PubMed Scopus (197) Google Scholar). It is also unclear whether the follow-up period was up to 8 months from the beginning or the completion of chemotherapy. In either case, considering the fact that resumption of menses can take 6 to 12 months due to the speed of follicle growth from primordial follicles, the follow-up period was too short. In fact, the authors did not provide a mean follow-up length or control for differences in the follow-up period. What concerns us the most is the authors' claim that GnRH-a is an effective method of fertility preservation when fertility was not even investigated. It is no surprise that a recent prospective randomized study in women with breast cancer proved this strategy to be ineffective (5Ismail-Khan R. Minton S. Cox C. Sims I. Lacevic M. Gross-King M. et al.Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: a randomized trial using the GnRH agonist (triptorelin) during chemotherapy [abstract].J Clin Oncol. 2008; 26: 15SGoogle Scholar). In that study, the data were controlled for age, receptor status, and treatment type. There was no difference in the percentage of patients menstruating 6, 12, and 18 months after chemotherapy in the GnRH-a group versus the controls (44% vs. 60%, 83% vs. 79%, and 88% vs. 84%, respectively). The trial was terminated at 18 months for ineffectiveness of the GnRH-a protocol. Furthermore, the FSH levels in the patients in whom menstruation has returned was not statistically significantly different in the GnRH-a group versus the control arm, and two spontaneous pregnancies occurred in the control group. Thus, the study by Badawy et al. (1Badawy A. Elnashar A. El-Ashry M. Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.Fertil Steril. 2009; 91: 694-697Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar) appears to have significant methodologic weaknesses and cannot be used as an evidence for the effectiveness of ovarian suppression for fertility preservation.