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Breast Cancer

How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries

Department of Obstetrics and Gynecology, Rambam Medical Center, Technion-Faculty of Medicine, Haifa, Israel

Key Words. Fertility preservation • Chemotherapy • Gonadotoxicity • GnRH-agonist • Premature ovarian failure

Correspondence: Zeev Blumenfeld, M.D., Department of Obstetrics and Gynecology, Rambam Medical Center, Technion-Faculty of Medicine, Haifa 31096, Israel. Telephone: 972-4-8542577; Fax: 972-4-8543746; e-mail: bzeev{at}techunix.technion.ac.il, z_blumenfeld{at}rambam.health.gov.il

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

The possibilities to preserve fertility in women exposed to chemotherapy are: in vitro fertilization plus embryo cryopreservation, ovarian cryopreservation, unfertilized ova cryopreservation, and the administration of a gonadotropin-releasing hormone (GnRH) agonist. Because none of these methods is ideal, combination of several methods should be considered. Because the chances of preserving gonadal function following combined-modality treatment are significantly better for girls than for boys, simulation of a prepubertal milieu was applied only to women of reproductive age. The administration of GnRH agonists to women with Hodgkin's disease, breast cancer, and other malignancies, or to patients with lupus nephropathy, in parallel with chemotherapy, by others and by us, has demonstrated a significantly lower rate of premature ovarian failure in survivors than in nonrandomized controls. Several prospective, randomized studies are ongoing. A recent meta-analysis found that the administration of a GnRH agonist, in addition to chemotherapy, to patients with breast cancer was associated with less recurrence and superior survival. Several possibilities to explain the beneficial effect of GnRH agonists to minimize chemotherapy-associated gonadotoxicity are suggested: (a) The hypogonadotropic milieu decreases the number of primordial follicles entering the differentiation stage, which is more vulnerable to chemotherapy; (b) The hypoestrogenic state decreases ovarian perfusion and delivery of chemotherapy to the ovaries; (c) A direct effect of the GnRH agonist on the ovary occurs independently of the gonadotropin level; (d) GnRH agonists may upregulate an intragonadal antiapoptotic molecule such as sphingosine-1-phosphate; (e) The GnRH agonist may protect ovarian germline stem cells.

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