No abstract

To examine whether the concomitant administration of a gonadotrophin-releasing hormone agonist (GnRHa) during combination chemotherapy to young women with lymphoma may facilitate preservation of gonadal function, a prospective clinical protocol was undertaken in 18 cycling women with lymphoma, aged 15-40 years. Thirteen patients suffered from Hodgkin disease (HD) and 5 from non-Hodgkin lymphoma. After informed consent a monthly injection of depot D-TRP6-GnRHa was administered for a maximum of 6 months starting prior to chemotherapy. Most of these patients (15/18) were treated with the MOPP/ABV(D) combination chemotherapy followed by mantle field irradiation in 10 patients. Hormonal profile [luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol, testosterone, progesterone, insulin-like growth factor (IGF)-1, prolactin] was taken before the GnRHa/chemotherapy co-treatment, and monthly thereafter until resuming spontaneous ovulation and menses. This group of prospectively treated lymphoma patients was compared to a matched control group of 18 women (aged 17-40 years) who have been treated with chemotherapy, mostly MOPP/ABV (14/18), with (11) or without (7) mantle field radiotherapy. Fourteen had Hodgkin's and four non-Hodgkin's lymphoma. Gonadal function was determined clinically, hormonally (LH, FSH, oestradiol, progesterone), and sonographically. Two of the patients in each group died from refractory disease. Of the remaining 16 patients, 15 (93.7%) resumed spontaneous ovulation and menses within 3-8 months of termination of the combined chemotherapy/GnRHa co-treatment. In contrast, only seven (39%) of the 18 similarly treated patients in the control group (chemotherapy without GnRHa) resumed ovarian cyclic activity (regular menses). The other 11 experienced premature ovarian failure (POF) (61%). Out preliminary data suggest a possible significant protective effect of GnRHa co-treatment with chemotherapy from irreversible ovarian damage (POF).

Our present results, extrapolating this encouraging experience from hematological malignant diseases to severe connective tissue diseases, such as SLE associated nephropathy or others, suggests that the beneficial effect of GnRH-a co-treatment may be exploited towards preservation of future fertility and ovarian function in every young woman of reproductive age, exposed to alkylating agents, such as cyclophosphamide and chlorambucil.

BACKGROUND: After the improved long-term survival in young women with lymphoma and leukemia undergoing chemotherapy, the preservation offuturefertility has been thefocus of recent interest. AREAS OF REVIEW: Three major topics are reviewed. They include the following: (1) the role of chemotherapy in the treatment of malignant and nonmalignant disease in young women, the types ofchemotherapy and their gonadal effects (differing between ovaries and testes) in both human and other species, and the reasons for differences in the outcomes of various studies; (2) the human experience with GnRH-agonist therapy for minimizing chemotherapy-associated gonadotoxicity; and (3) inhibin measurements in young women treated by chemotherapy and in perimenopausal patients and those with impending premature ovarian failure (POF).Whereas egg retrievalfor in vitrofertilization (IT7F) and embryo cryopreservation is a valid assisted reproductive technology (ART)for married couples, it may be unacceptablefor the young single woman. The investigational endeavors of ovarian cryopreservation awaits the clinical experience of in vitro maturation of thawed primordial follicles, their IT7F, and embryo transfer. Although promising, this experience is not yet available. Moreover, the risk ofpossible reimplantation of malignant stem cells with the thawed cryopreserved ovary has been raised after animal observations. Therefore, until these innovative endeavors prove successful, and in parallel with them, an attempt was made to minimize the gonadotoxic effect ofchemotherapy by the cotreatment with a GnRH agonistic analogue (GnRH-a) to induce a temporary prepubertal milieu, because prepubertal ovaries were found more resistant to alkylating agents' effect than the ovaries of older women. To characterize the correlation with ovarian function after gonadotoxic chemotherapy for Hodgkin or non-Hodgkin lymphoma in young women, the immunoreactive inhibin-A concentrations in the sera of these patients were measured before, during, and after the gonadotoxic chemotherapy. CONCLUSIONS: The GnRH-a cotreatment should be considered in every woman in the reproductive age receiving chemotherapy, in addition to ART and the investigational attempts of ovarian cryopreservationfor future in vitro maturation or reimplantation. If these preliminary data are confirmed in a larger group of patients, inhibin-A concentrations may serve as a prognosticfactorfor predicting the resumption of ovarian function in addition to the levels of FSH, LH, and estradiol.