Preservation of fertility and ovarian function and minimalization of chemotherapy associated gonadotoxicity and premature ovarian failure: the role of inhibin-A and -B as markers.
BACKGROUND
Following the improved long term survival in young women with lymphoma and leukemia undergoing chemotherapy, the preservation of future fertility has been the focus of recent interest. The investigational endeavors of ovarian cryopreservation awaits the clinical experience of in-vitro maturation of thawed primordial follicles, their in-vitro fertilization and ET. Although promising, this experience is not available yet. Moreover, the risk of possible reimplantation of malignant stem cells with the thawed cryopreserved ovary has been raised, following experimental animal observations. Therefore, until these innovative endeavors prove successful, and in parallel to them we attempted to minimize the gonadotoxic effect of chemotherapy by the co-treatment with a 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. The immunoreactive inhibin-A and -B in these patients, before, during, and following the gonadotoxic chemotherapy were measured.


METHODS
A prospective clinical protocol was undertaken in 55 women with lymphoma, aged 15-40 years, ten with leukemia and eight undergoing chemotherapeutic treatments for non malignant diseases such as systemic lupus erythematosus (SLE) or other autoimmune diseases. A monthly injection of depot D-TRP6-GnRH-a was administered from before starting the chemotherapy until its conclusion, up to a maximum of 6 months. Hormonal profile (FSH, LH, E2, T, P4, IGF-1, IGF-BP3, and PRL) was taken before starting the GnRH-a/chemotherapy co-treatment, and monthly thereafter, until resuming spontaneous ovulation. This group was compared with a control group of 55 women who have been treated with similar chemotherapy. Inhibin-A and -B immunoactivity was measured by an ELISA commercial kit (Serotec).


RESULTS
Whereas, all but three (40- and 36-year-old) of the surviving patients with GnRH-a/chemotherapy co-treatment group resumed spontaneous ovulation and menses within 12 months, less than half of the patients in the control group (chemotherapy without GnRH-a co-treatment) resumed ovarian function and regular cyclic activity (P<0.05). The remaining 56% experienced premature ovarian failure (POF). Temporary increased FSH concentrations were experienced by about 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 the GnRH-a/chemotherapy co-treatment but increased to normal levels in patients who resumed regular ovarian cyclicity, and/or spontaneously conceived, as 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 for predicting the resumption of ovarian function, in addition to the levels of FSH, LH and E2. The GnRH-a co-treatment should be considered in every woman in the reproductive age receiving chemotherapy, in addition to ART, and to the investigational attempts of ovarian cryopreservation for future in-vitro maturation, autotransplantation, or xenotransplantation.
Blumenfeld
Z
Z
Reproductive Endocrinology and Infertility Section, Department of Obstetrics and Gynecology, Rambam Medical Center, Technion-Faculty of Medicine, Technion-Israel Institute of Technology, 31096, Haifa, Israel. bzeev@techunix.technion.ac.il
D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control*; D007265:Inhibins / Q000097:blood; D010053:Ovary / Q000187:drug effects / Q000502:physiology; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control
D000970:Antineoplastic Agents; D015415:Biomarkers; C422362:inhibin A; C422364:inhibin B; D007265:Inhibins