Ovarian rescue/protection from chemotherapeutic agents.
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 endeavors 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 chemotherapeutic treatments for nonmalignant diseases such as systemic lupus erythematosus or other autoimmune diseases. A monthly 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 monthly thereafter 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 hormone (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.
Reproductive Endocrinology Section, Department of Ob/Gyn, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. bzeev@techunix.technion.ac.il
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Blumenfeld
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy; D005260:Female; D006801:Humans; D007265:Inhibins / Q000097:blood; D007938:Leukemia / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced* / Q000517:prevention & control*; D011446:Prospective Studies; D017329:Triptorelin Pamoate / Q000008:administration & dosage
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D017329:Triptorelin Pamoate; D007265:Inhibins