Prevention of gonadal damage during cytotoxic therapy.
Infertility represents one of the main remote sequelae of cytotoxic chemotherapy given for various malignant diseases. The impairment of gonadal function after cytotoxic chemotherapy is more frequent in the male than in the female. Because dividing cells are more sensitive to the cytotoxic effects of alkylating agents than are cells at rest, it has been hypothesized that inhibition of the pituitary-gonadal axis by gonadotropin-releasing hormone (GnRH) agonists would render the germinal epithelium less susceptible to the cytotoxic effects of chemotherapy. This hypothesis has not been thoroughly clinically tested until recently, although several investigators have demonstrated that GnRH-agonistic analogues (GnRH-a) inhibit chemotherapy-induced ovarian follicular depletion in the rat and Rhesus monkeys. Based on this rationale, we have undertaken a prospective evaluation to determine whether GnRH-a administration during combination chemotherapy for Hodgkin's and non-Hodgkin's lymphoma could prevent posttreatment ovarian damage in women by inducing a temporary prepubertal hormonal milieu. While over 93% of the surviving patients in the GnRH-a and chemotherapy group resumed spontaneous ovulation and menses, less than 40% of the women in the control group of chemotherapy without the GnRH-a cotreatment resumed normal ovarian cyclic activity. More than 60% of the women experienced premature ovarian failure (POF) in the chemotherapy alone group. Our preliminary results suggest that GnRH-a cotreatment protects against POF during cytotoxic chemotherapy. The GnRH-a and chemotherapy cotreatment may be also suggested for young women treated by cyclophosphamide pulse therapy or other gonadotoxic treatments for systemic lupus erythematosus, organ transplantation and other autoimmune diseases. The technology of cryopreservation of human ova for future fertility in these patients awaits clinical validation and substantiation. This review discusses possibilities to prevent gonadal damage induced by cytotoxic therapy and presents the clinical data currently available.
Blumenfeld
Z
Z
Department of Obstetrics and Gynecology, Rambam Medical Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. bzeev@techunix.technion.ac.il
Haim
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006689:Hodgkin Disease / Q000188:drug therapy; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008253:Macaca mulatta; D008297:Male; D010053:Ovary / Q000187:drug effects*; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D013737:Testis / Q000187:drug effects
D000970:Antineoplastic Agents; D007987:Gonadotropin-Releasing Hormone