Preservation of Fertility and Ovarian Function and Minimizing Chemotherapy-Induced Gonadotoxicity in Young Women

Abstract

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.

Tamoxifen decreases ovarian follicular loss from experimental toxicant DMBA and chemotherapy agents cyclophosphamide and doxorubicin in the rat

“…Although some patients are currently able to preserve their fertility during cancer treatment by embryonic cryopreservation [3][4][5], ovaries remain in situ and exposed to chemotherapy drugs in nearly all patients. GnRH agents have been tested as ovarian protectants with mixed results [6][7][8][9][10]. An alternative conservative strategy to protect the ovary from cytotoxic therapy is needed to maintain not only oocyte quality but also hormone production for the support of follicle growth and pregnancy.…”

Use of gonadotropin-releasing hormone agonists in patients with Hodgkin’s disease for preservation of ovarian function and reduction of gonadotoxicity related to chemotherapy

“…Preliminary clinical trials have shown that the administration of gonadotropin-releasing hormone agonists (GnRH-a) to young women during the standard chemotherapy regimes resulted in resumption of ovarian function in a significant percentage of patients after termination of treatment (2,9,10). However, previous studies on the use of GnRH-a in association with chemotherapy in young patients with malignancies included heterogeneous groups of women with different diseases.…”

“…This increase in survival is a result of the introduction of effective chemotherapy, such as when MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) and/or ABVD (adriamycin, bleomycin, vinblastine, and decarbazine) and its variants are used (3). Although the cytotoxic effect of these treatments is reversible in tissues with rapidly dividing cells such as bone marrow, the gastrointestinal tract, and thymus (4), it appears to be progressive and irreversible in the ovary, in which germ cells are limited in number and cannot be regenerated (1,2,5).…”

“…No significant differences were observed in bone mineral density between groups. At present, the survival of young patients treated with cytotoxic chemotherapy for Hodgkin's disease, the most frequent malignancy in the 15-to 29-year-old population (1)(2)(3), is nearly 90%. This increase in survival is a result of the introduction of effective chemotherapy, such as when MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) and/or ABVD (adriamycin, bleomycin, vinblastine, and decarbazine) and its variants are used (3).…”

GnRH-Analoga

“…Blumenfeld und Mitarbeiter sowie Howell und Recchia konnten in einigen Studien mit kurzem Follow-up durch Gabe von GnRH-Analoga vor und während der Chemotherapie bei jungen Frauen mit malignen Erkrankungen eine protektive Wirkung auf die Ovarialfunktion nachweisen [3,5,6,7,8,13,23]. Allerdings macht die retrospektive Analyse der Kontrollgruppe die Beobachtungen weniger aussagekräftig.…”