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Ovarian Rescue/Protection from Chemotherapeutic Agents

Reproductive Endocrinology Section, Departments of Ob/Gyn, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Technion-Israel Institute of Technology, Ministry of Health, and the A. Tufeld Cancer Research Fund; Reproductive Endocrinology and Infertility Section, Department of Obstetrics and Gynecology, Technion-Faculty of Medicine, Rambam Medical Center, Haifa 31096, Israel; bzeev{at}techunix.technion.ac.il

Background: After improved long-term survival in young women with lymphoma and leukemia undergoing chemotherapy, preservation of future fertility has been the focus of recent interest. The investigational endevors of ovarian cryopreservation await the clinical experience of in vitro maturation of thawed primordial follicles, their in vitro fertilization, and embryo transfer. Although promising, this experience is not yet available. Moreover, the risk of possible reimplantation of malignant stem cells with the thawed cryoperserved ovary has been raised after experimental animal observations. Therefore, until these innovative endeavors prove successful, and in parallel with them, we attempted to minimize the gonadotoxic effect of chemotherapy by the cotreatment with a gonadotropin-releasing hormone (GnRH) agonistic analogue to induce a temporary prepubertal milieu. Whereas inhibin-B concentrations in serum may reflect the ovarian granulosa cell compartment, inhibin-A reflects luteal function. Immunoreactive inhibin-A and -B in these patients before, during, and after gonadotoxic chemotherapy were measured.

Methods: A prospective clinical protocol was undertaken in 44 women with lymphoma, aged 15-40 years, ten with leukemia and eight undergoing cehmotherapeutic treatments for nonmalignant diseases such as systemic lupus erythematosus or other autoimmune diseases. A montly injection of depot D-TRP6-GnRH-a was administered from before the start of chemotherapy until its conclusion, up to a maximum of 6 months. A hormonal profile was taken before starting the GnRH-a/chemotherapy cotreatment, and montly therafter until the women resumed spontaneous ovulation. This group was compared with a control group of 55 women who had been treated with similar chemotherapy. Inhibin-A and -B immunoactivity was measured.

Results: Whereas all but one (40-year-old) of the surviving patients with GnRH-a/chemotherapy cotreatment group resumed spontaneous ovulation and menses within 6 months, fewer than half of the patients in the control group (chemotherapy without GnRH-A cotreatment) resumed ovarian function and regular cyclic activity (P < .05). The remaining 60% experienced premature ovarian failure (POF). Temporary increased follicle-stimulating homroe (FSH) concentrations were experienced by almost a third of the patients resuming cyclic ovarian function, suggesting a reversible ovarian damage in a larger proportion of women than those experiencing POF. Inhibin-A and -B decreased during GnRH-a/chemotherapy cotreatment but increased to normal levels in patients who resumed regular ovarian cyclicity and/or spontaneously conceived, compared with low levels in those who developed POF.

Conclusions: If these preliminary data are consistent in a larger group of patients, inhibin-A or -B concentrations may serve as prognostic factors to predict the resumption of ovarian function, in addition to the levels of FSH, luteinizing hormone, and estradiol. GnRH-a cotreatment should be considered for every woman of reproductive age who receives chemotherapy, in addition to assisted reproductive technology and the investigational attempts of ovarian cryopreservation for future in vitro maturation.

Key Words: Inhibin-A and -B • gonadotoxicity • premature ovarian failure • hypergonadotropic amenorrhea • chemotherapy • GnRH-a

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