Skip to main content
Download PDF
  • Fertilité Après Traitement Anti-Cancéreux
  • Préserver la Fertilité: Pourquoi?
  • Published:

Conséquences de la chimiothérapie anticancéreuse sur la fertilité de la femme

Ovarian dysfunction in young cancer women who receive cytotoxic chemotherapy

Andrologie volume 14, pages 392–397 (2004)Cite this article

Resume

Le risque de stérilité par la chimiothérapie reste mal précisé, il est assez bien établi pour les alkylants, moins bien précisé pour les anthracyclines, le methotrexate et le fluoro-uracile et mal défini pour les alcaloïdes, les platines, l’etoposide, les taxanes. Les facteurs déterminants de la toxicité sont l’effet additif des drogues, les doses cumulées et l’âge des patientes. Le retentissement de la chimiothérapie sur la lignée germinale est étudié sur les cycles menstruels, les dosages hormonaux et les grossesses.

La chimiothérapie entraîne une destruction des ovocytes et des cellules de la granulosa. L’adriamycine entraîne chez la souris une apoptose ovocytaire qui pourrait être prévenue par une manipulation des signaux du cycle cellulaire (dérégulation du gène Bax, expression du gène antagoniste Bcl-2, utilisation de sphingosine-1-phosphate ou de peptides inhibiteurs des caspases).

Les données cliniques de la littérature sont confuses et habituellement rétrospectives. A titre d’exemple la fertilité globale après chimiothérapie MOPP pour maladie de Hodgkin est de l’ordre de 20%, les chimiothérapies adjuvantes du cancer du sein avec CMF, F(A)C (fluorouracile anthracycline cyclophosphamide) ou TAC entraînent de 50 à 70% d’aménorrhées, la chimiothérapie de type PVB ou BEP pour tumeur germinale overienne altère relativement peu les possibilités de grossesses si un ovaire a pu être conservé et une majorité de femmes traitées par chimiothérapie pour maladie trophoblastique persistante avec methotrexate, actinomycine ou associations diverses restent fertiles.

La prévention de la fertilité est un enjeu thérapeutique majeur: les techniques de FIV sont rarement applicables en raison du retard qu’elles entraînent à la mise en route de la chimiothérapie; la conservation d’ovocytes est en phase de recherche; les contraceptifs oestroprogestatifs n’ont pas montré d’efficacité, par contre les agonistes de GnRH pourraient être utiles, ils sont capables de prévenir la toxicité du cyclophosphamide sur l’ovogenèse chez la ratte et le singe macaque Rhésus et quelques études pilotes invitent à réaliser des études randomisées.

Abstract

Sterility is a potential toxic effect of chemotherapy. This risk is well established for alkylating agents, but is less clearly defined for anthracyclines, methotrexate and fluorouracil and poorly defined for alkaloids, platinum, etoposide and taxanes. The main predictive factors for ovarian toxicity are the additive effect of cytotoxic drugs, the cumulative dose of each drug and the patient’s age. This effect of chemotherapy is evaluated on menstrual cycles, hormonal assays and the number of pregnancies observed in patient cohorts.

Chemotherapy induces destruction of oocytes and granulosa cells. In mice, it has been shown that adriamycin may induce oocyte apoptosis, which can be prevented by modulation of cycle cell signalling (dysregulation of Bax gene or, on the contrary, expression of its antagonist gene Bcl-2 or inhibition of apoptosis with sphingosine-1-phosphate or caspase inhibitors). Clinical data in the literature are usually based on retrospective studies and are somewhat confused: global fertility after MOPP chemotherapy for Hodgkin’s disease is about 20%, adjuvant chemotherapy with CMF, F(A)C or TAC for breast cancer induces amenorrhea in 50% to 70% of cases, PVB or BEP chemotherapy for ovarian germ cell tumors has little effect on fertility when the uterus and one ovary can be preserved, and the majority of women treated with methotrexate, actinomycin D or various combinations for persistent trophoblastic disease remain fertile.

Preservation of fertility is a major goal for cancer patients receiving chemotherapy: in vitro fertilization could preserve the couple’s fertility, but is usually not feasible as it would delay initiation of chemotherapy until after stimulation of ovulation; oocyte or ovarian tissue cryopreservation is at the stage of research; oral contraceptives have not been demonstrated to be effective to preserve ovarian function; gonadotropin releasing hormone (GnRH) agonists prevent cyclophosphamide toxicity in rat and monkey ovaries, and a few pilot clinical studies suggest that chemotherapy-induced amenorrhea could be prevented by administration of GnRH analogues simultaneously to chemotherapy, but randomised studies are necessary.

References

  1. ANDRIEU J.M., OCHOA-MOLINA M.E.: Pregnancies and offspring after MOPP therapy. Nouv. Presse Med., 1982, 11: 3623–3625.

    PubMed  CAS  Google Scholar 

  2. ANDRIEU J.M., OZANNE F., DANA M. et al.: Multiple chemotherapy (MOPP) followed by either focal or selective radiotherapy in clinical stages IA and II2A of Hodgkin’s disease: results after four years of the use of prospective schedule (H 7701) in 79 patients (author’s trans). Bull. Cancer, 1981, 68: 217–223.

    PubMed  CAS  Google Scholar 

  3. ATAYA K., RAO L.V., LAWRENCE E., KIMMEL R.: Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol. Reprod., 1995, 52: 365–372.

    Article  PubMed  CAS  Google Scholar 

  4. BINES J., OLESKE D.M., COBLEIGH M.A.: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J. Clin. Oncol., 1996, 14: 1718–1729.

    PubMed  CAS  Google Scholar 

  5. BLUMENFELD Z., DANN E., AVIVI I., EPELBAUM R., ROWE J.M.: Fertility after treatment for Hodgkin’s disease. Ann. Oncol., 2002, 13 (Suppl 1): 138–147.

    PubMed  Google Scholar 

  6. BONADONNA G., VALAGUSA P., SANTORO A., VIVIANI S., BONFANTE V., BANFI A.: Hodgkin’s disease: the Milan Cancer Institute experience with MOPP and ABVD. Recent Results Cancer Res., 1989, 117: 169–174.

    PubMed  CAS  Google Scholar 

  7. CHAPMAN R.M., SUTCLIFFE S.B., MALPAS J.S.: Cytotoxic-induced ovarian failure in women with Hodgkin’s disease. I. Hormone function. J. Am. Med. Ass., 1979, 242: 1877–1881.

    Article  CAS  Google Scholar 

  8. CHAPMAN R.M. In: DeVita V.T., Hellman J.S., Rosenberg S.A. eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia, J.B. Lippincott, 1993.

    Google Scholar 

  9. FRANCHI-REZGUI P., ROUSSELOT P., ESPIE M. et al.: Fertility in young women after chemotherapy with alkylating agents for Hodgkin and non-Hodgkin lymphomas. Hematol. J., 2003, 4: 116–120.

    Article  PubMed  CAS  Google Scholar 

  10. HORNING S.J., HOPPE R.T., KAPLAN H.S., ROSENBERG S.A.: Female reproductive potential after treatment for Hodgkin’s disease. N. Engl. J. Med., 1981, 304: 1377–1382.

    PubMed  CAS  Google Scholar 

  11. KOZINER B., MYERS J., CIRRINCIONE C. et al.: Treatment of stages I and II Hodgkin’s disease with three different therapeutic modalities. Am. J. Med., 1986, 80: 1067–1078.

    Article  PubMed  CAS  Google Scholar 

  12. KREUSER E.D., XIROS N., HETZEL W.D., HEIMPEL H.: Reproductive and endocrine gonadal capacity in patients treated with COPP chemotherapy for Hodgkin’s disease. J. Cancer Res. Clin. Oncol., 1987, 113: 260–266.

    Article  PubMed  CAS  Google Scholar 

  13. LOVAS S., PALYL I., VINCZE B., HORVATH J. et al.: Direct anticancer activity of gonadotropin-releasing hormone-III. J. Pept. Res., 1998, 52: 384–389.

    PubMed  CAS  Google Scholar 

  14. MORRA E., LAZZARINO M., INVERARDI D. et al.: Therapyrelated ovarian dysfunction in women treated for Hodgkin’s disease. Haematologica, 1986, 71: 209–215.

    PubMed  CAS  Google Scholar 

  15. OKTAY K., BUYUK E., DAVIS O., YERMAKOVA I., VEECK L., ROSENWAKS Z.: Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum. Reprod., 2003, 18: 90–95.

    Article  PubMed  CAS  Google Scholar 

  16. OKTAY K., BUYUK E., VEECK L. et al.: Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet, 2004, 363: 837–840.

    Article  PubMed  Google Scholar 

  17. ORTIN T.T., SHOSTAK C.A., DONALDSON S.S.: Gonadal status and reproductive function following treatment for Hodgkin’s disease in childhood: the Stanford experience. Int. J. Radiat. Oncol. Biol. Phys., 1990, 19: 873–880.

    PubMed  CAS  Google Scholar 

  18. PEREYRA P.B., MENDEZ RIBAS J.M., MILONE G. et al.: Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report. Gynecol. Oncol., 2001, 81: 391–397.

    Article  Google Scholar 

  19. PEREZ G.I., KNUDSON C.M., LEYKIN L., KORSMEYR S.J., TILLY J.L.: Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction. Nat. Med., 1997, 3: 1228–1232.

    Article  PubMed  CAS  Google Scholar 

  20. SCHILSKY R.L., SHERINS R.J., HUBBARD S.M., WESLEY M.N., YOUNG R.C., DEVITA V.T.: Long-term follow up of ovarian function in women treated with MOPP chemotherapy for Hodgkin’s disease. Am. J. Med., 1981, 71: 552–556.

    Article  PubMed  CAS  Google Scholar 

  21. TANGIR J., ZELTERMAN D., MA W., SCHWARTZ P.E.: Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet. Gynecol., 2003, 101: 251–257.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre Léon Bérard, 28 rue Laënnec, 69008, Lyon

    Jean Paul Guastalla

Authors
  1. Jean Paul Guastalla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean Paul Guastalla.

Additional information

Communication au Colloque de la Fédération des CECOS, Lyon, 18 mars 2004.

Préserver la fertilité des patients soumis à des traitements anticancéreux: la cryopréservation des gamètes et du tissu gonadique.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guastalla, J.P. Conséquences de la chimiothérapie anticancéreuse sur la fertilité de la femme. Androl. 14, 392–397 (2004). https://doi.org/10.1007/BF03035170

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03035170

Mots clés

Key words

Basic and Clinical Andrology

ISSN: 2051-4190