Protocol combining GnRH agonists and GnRH antagonists for rapid suppression and prevention of gonadal damage during cytotoxic therapy

Purpose of investigation: Infertility represents one of the main sequelae of cytotoxic therapy given for various malignant diseases. Because dividing cells are more sensitive to cytotoxic effects than are cells at rest, it has been hypothesized that inhibition of the pituitary-gonadal axis may facilitate the preservation of future gonadal function. The aim of our study was to find a quick, reliable and economic way to suppress the pituitary-gonadal axis by combining GnRH-agonists with GnRH-antagonists in order to preserve future gonadal function.

Methods: A combination of D-Trp6-GnRH-a (3.75 mg) and cetrorelix (3 mg) was used to achieve a quick downregulation in six postmenarchal young women (aged 15.4 +/- 0.7) years with haematological malignancies before the onset of cytotoxic chemotherapy.

Results: The combination of D-Trp6-GnRH-a and GnRH-antagonist cetrorelix induced a reliable and long-lasting suppression of gonadotrophin secretion within 96 hours in all patients allowing cytotoxic therapy to be started without any delay.

Conclusions: The combination of GnRH-agonist and GnRH-antagonist enables a rapid, reliable and cost-effective suppression of the pituitary-gonadal axis to be achieved. Future gonadal function of treated patients will be monitored.

Chemotherapy; GnRH-analogues; Gonadotoxicity, Fertility

[1] Janson P.O.: "Possibilities of fertility preservation in children and young adults undergoing treatment for malignancy". Acta Obstet. Gynecol. Scand., 2000, 79, 240.

[2] Blumenfeld Z., Avivi I., Ritter M., Rowe J.M.: "Preservation of fertility and ovarian function and minimizing chemotherapyinduced gonadotoxicity in young women". J. Soc. Gynecol. Invest., 1999, 6, 229.

[3] Blumenfeld Z., Haim N.: "Prevention of gonadal damage during cytotoxic therapy". Ann. Med., 1997, 29, 199.

[4] Glaser S.L.: "Reproductive factors in Hodgkin disease m women: a review". Am. J. Epidemiol., 1994, 139, 237.

[5] Sutcliff S.B.: "Cytotoxic chemotherapy and gonadal function in patients with Hodgkin disease". JAMA, 1979, 242, 1898.

[6] Broekmans F.J., Bernardus R.E., Broesers A.: "Pituitary responsiveness after administration of a GnRH agonist depot formulation: Decapeptyl CR". Clinical Endocrinology, 1993, 38, 579.

[7] Coy D.H., Labrie F., Savary M.: "LH releasing activity of potent LH-RH analogues in vitro". Biochem. Biophys. Res. Comm., 1975, 65, 576.

[8] Adashi E.Y.: "The ovarian follicular apparatus". In: Adashi E.Y., Rock J.A., Rosenwaks Z. (eds.). Reproductive Endocrinology, Surgery and Technology. Philadelphia, Lippincott Raven, 1996, 17.

[9] Familiari G., Caggiati A., Nottola S.A., Ermini M.,D i Bendetto M.R., Motta P.M.: "Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin's disease". Hum. Reprod., 1993, 8, 2080.

[10] Ataya K., Moghissi K.: "Chemotherapy induced premature ovarian failure: mechanisms and prevention". Steroids, 1989, 54, 607.

[11] Bokser L., Szende B., Schally A.V.: "Protective effects ofD-Trp6- LHRH microcapsules against cyclophosphamide - induced gonadotoxicity in female rats". Br. J. Cancer, 1990, 61, 861.

[12] Ataya K., Rao L.V., Lawrence E., Kimmel R.: "Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamideinduced ovarian follicular depletion in rhesus monkeys". Biol. Reprod., 1995, 52, 365.

[13] Blumenfeld Z., Avivi I., Linn S., Epelbaum R., Ben-Shahar M., Haim N.: "Prevention of irreversible chemotherapy induced ovarian damage in young women with lymphoma by gonadotrophin-releasing hormone agonist i n parallel to chemotherapy". Hum. Reprod., 1996, 11, 1620.