Reply of the authors: Evidence-based medicine or just a theory?

LETTER TO THE EDITOR Reply of the authors: We agree with Kol et al. that despite three decades having elapsed since the introduction of the hypothesis that GnRH analogues (GnRH-a) may preserve fertility, not a single randomized study has proved that hypothesis. In contrast, two randomized studies proved the opposite (1, 2). In the most recent randomized study, which was performed in 44 women with breast cancer, patients were assigned randomly to a GnRH-a versus no treatment during breast cancer chemotherapy (2). After 18 months of follow-up the percentage of patients who resumed menstruation was similar (88% vs. 84%). Only two pregnancies occurred, and those were in the control group. Furthermore, serum FSH and E2 levels were also similar between the groups. Authors then concluded that GnRH-a treatment does not protect ovarian function or fertility and stopped the study at that point. Despite the evidence from experimental data, Blumenfeld et al. (3) continue to cite observational data and uncontrolled studies to defend a biologically implausible treatment. For example, they cite a pregnancy after bone marrow transplantation claiming this as a proof of GnRHa effectiveness. As Blumenfeld et al. pointed out, spontaneous pregnancies may occur after bone marrow transplantation. Further Blumenfeld et al. (3) cite another nonrandomized study in which baseline ovarian assessment before enrollment was made on FSH and LH measurements on day 1 through 5, and normal ovarian function postchemotherapy was determined as the presence of regular menstrual bleeding and on the basis of serum FSH and LH <15 IU/L (4). Ovarian reserve assessment should include not only FSH, but also serum E2 and antral follicle counts, as well as antim€ ullerian hormone levels. It is well established that in women with severely diminished ovarian reserve, E2 levels rise prematurely and suppress FSH levels, and thus measurement of FSH levels only will yield a false impression of normal ovarian reserve. Moreover, in the study of Huser et al. (4) GnRH-a cotreatment was demonstrated ineffective when higher doses of combination chemotherapy were given, as was clearly demonstrated in childhood cancers. Although Blumenfeld et al. (3) cited a rodent study by Ataya et al. (5) that found GnRH-a effective, another primate study by the same group proved the opposite in rhesus monkeys treated by radiation and was not mentioned. Because of space limitation we could not reference the study by Letterie (6) in our previous letter (7) in which ovarian suppression clearly was demonstrated ineffective against chemotherapy in rodents. Although Blumenfeld et al. (3) continue to argue that GnRH-a protects ovarian function, even by their account there has not been a single study demonstrating that GnRH-a preserves fertility. They also suggest that, because there is no randomized comparison comparing oocyte or embryo cryopreservation with no interventions, the success of these tech-

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niques is unproved. Given tens of thousands of children born from embryo and oocyte freezing, this would be an unethical study. As Kol et al. suggested, it is time that Blumenfeld et al. acknowledge the flaws in thinking leading to the misconception of GnRH-a as a fertility preservation drug and turn to prospective randomized studies as a source of proof where women are offered GnRH-a versus placebo in addition to effective proved strategies such as embryo and oocyte freezing, with the primary outcome being fertility. Kutluk Oktay, M.D. Institute for Fertility Preservation Department of Obstetrics and Gynecology New York Medical College Valhalla, New York Murat So¨nmezer, M.D. Department of Obstetrics and Gynecology Ankara University School of Medicine Ankara University Center for Research on Human Reproduction Ankara, Turkey Kenny Rodriguez Wallberg, M.D., Ph.D. Fertility Preservation Program Fertility Unit Karolinska University Hospital Stockholm, Sweden March 16, 2009 REFERENCES 1. Waxman JH, Ahmed R, Smith D, Wrigley PF, Gregory W, Shalet S, et al. Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 1987;19:159–62. 2. Ismail-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 GnRH agonist (triptorelin) during chemotherapy [abstract]. J Clin Oncol 2008;26(May 20 Suppl):524. 3. Blumenfeld Z, Avivi I, Eckman A, Epelbaum R, Rowe JM, Dann EJ. Gonadotropin-releasing hormone agonist decreases chemotherapyinduced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril 2008;89:166–73. 4. Huser M, Crha I, Ventruba P, Hudecek R, Zakova J, Smardova L, et al. Prevention of ovarian function damage by a GnRH analogue during chemotherapy in Hodgkin lymphoma patients. Hum Reprod 2008;23:863–8. 5. Ataya K, Pydyn E, Ramahi-Ataya A, Orton CG. Is radiation-induced ovarian failure in rhesus monkeys preventable by luteinizing hormone–releasing hormone agonists?: preliminary observations. J Clin Endocrinol Metab 1995;80:790–5. 6. Letterie GS. Anovulation in the prevention of cytotoxic-induced follicular attrition and ovarian failure. Hum Reprod 2004;19:831–7. 7. Oktay K, Sonmezer M, Barad D, Gleicher N. Trying to reduce ovarian damage in patients with Hodgkin lymphoma using GnRH agonists? [letter]. Fertil Steril 2009;91:298–9.

doi:10.1016/j.fertnstert.2009.03.071

Fertility and Sterility Vol. 92, No. 1, July 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.

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