Konsensus der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG)/Arbeitsgemeinschaft für Gynäkologische Onkologie

Zusammenfassung

Fragestellung: Die OEGGG/AGO hat den Themenkomplex Fertilität, Kontrazeption und Hormonersatz bei onkologischen Erkrankungen aktuell bearbeitet und stellt ein Konsensuspapiers vor. Fertilität: Am stärksten gonadotoxisch wirken Alkylanzien. Tamoxifen und Aromatasehemmer üben nur einen marginalen Einfluss auf die ovarielle Reserve aus. GnRH-Analoga schädigen Keimzellen nicht. Mit zunehmendem Lebensalter einer Frau nimmt die ovarielle Reserve und damit die Wahrscheinlichkeit, schwanger zu werden, kontinuierlich ab. Eine systemische Chemotherapie beschleunigt den physiologischen Vorgang der Reduktion von Primordialfollikeln unabhängig vom Lebensalter. Nach dem Abschluss einer Chemotherapie bzw. Antihormontherapie sollte zumindest 2 Monate abgewartet werden, um die Ovarialfunktion zu beurteilen. Dazu müssen auch biochemische Analysen herangezogen werden. Der zuverlässigste Parameter ist in dieser Hinsicht das Anti-Müller-Hormon (AMH; Muellerian Inhibiting Factor, MIF), da AMH während des gesamten Zyklus einen stabilen Parameter darstellt. FSH- und Inhibin-B-Werte stellen lediglich Momentaufnahmen dar. Die Datenlage zur Medikation mit GnRH-Analoga parallel zur Chemotherapie zum Fertilitätserhalt ist derzeit noch nicht konklusiv. Die Methode der Ruhigstellung der Ovarien durch Ovulationshemmer hat sich v.a. bei hämatologischen Neoplasien wie dem Morbus Hodgkin als effektiv erwiesen. „Ovarian tissue banking“ und Methoden der assistierten Reproduktion sind als experimentell anzusehen und dürfen nur in zertifizierten Zentren angeboten werden. Ähnliches gilt für eine In-vitro-Fertilisierung vor der Chemotherapie („Emergency IVF“). Kontrazeption: Bei allen Malignomen mit Ausnahme des Mammakarzinoms können sämtliche gängige Methoden der Kontrazeption eingesetzt werden. Beim Mammakarzinom wird generell die Anwendung eines Kupfer-Intrauterinpessars empfohlen. Tamoxifen ist kein Kontrazeptionsschutz. Werden aus onkologischer Sicht GnRH-Analoga verordnet, ist für die Dauer der GnRH-Gabe keine zusätzliche Maßnahme zur Kontrazeption notwendig.

Abstract

A working group of the OEGGG/AGO presents a consensus statement on fertility, contraception and hormone replacement therapy in oncologic patients. Fertility: Alkylating agents are the most gondadotoxic. Tamoxifen and aromatase inhibitors exert only a marginal influence on ovarian reserve. GnRH analogues do not damage germ cells. Increasing age is associated with reduced ovarian reserve and the probability of pregnancy. Systemic chemotherapy accelerates the physiological process of reduction of primordial follicles independently of age. Following cytotoxic or antihormonal treatment, ovarian function tests should not take place earlier than 2 months. Biochemical analyses should be included also. With regard to ovarian reserve, the most reliable parameter is the anti muellerian hormone (AMH; Muellerian Inhibiting factor, MIF) since its value remains stable throughout the cycle. This is not true for FSH and inhibin beta. Data on the medication with GnRH analogues in parallel to chemotherapy for fertility preservation are inconclusive. The method of ovulation inhibition via contraceptives has been shown effective mainly in hematologic diseases such as Hodgkin's disease. Ovarian tissue banking and methods of assisted reproduction can be considered experimental and thus may only be offered in certified centers. Similarly, in vitro fertilisation before chemotherapy (“emergency IVF”) is experimental. Contraception: The main methods of contraception can be used by all oncologic patients with the exception of breast cancer in which generally the placement of an intrauterine pessar is recommended. Tamoxifen is no contraceptive method. If, from the oncologic point of view, GnRH agonists are prescribed, no additional contraception is necessary.

Schlüsselwörter

Fertilität - Kontrazeption - Hormonersatz - onkologische Erkrankungen - Brustkrebs - Konsensus - ovarielle Reserve - Chemotherapie - GnRH‐Analoga

Key words

fertility - contraception - hormone replacement therapy - oncologic diseases - breast cancer - consensus - ovarian reserve - chemotherapy - GnRH analogues

Literatur

• 1 Barakat R, Bundy B, Spirtos N et al. Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I and II endometrial cancer: A Gynecologic Oncology Group study.  J Clin Oncol. 2006;  24 587-592
• 2 Behringer K, Breuer K, Reineke T et al. Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: A report from the German Hodgkin's lymphoma study group.  J Clin Oncol. 2005;  23 7555-7564
• 3 Beiner M, Covens A. Surgery insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer.  Nat Clin Pract Oncol. 2007;  4 353-361
• 4 Blumenfeld Z, Avivi I, Linn S et al. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotropin-releasing hormone agonist in parallel to chemotherapy.  Hum Reprod. 1996;  11 1620-1626
• 5 Blumenfeld Z, Avivi I, Eckman A. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin's lymphoma.  Fertil Steril. 2008;  89 166-173
• 6 Brewer M, Gershenson D, Herzog C et al. Outcome and reproductive function after chemotherapy for ovarian dysgerminoma.  J Clin Oncol. 1999;  17 2670-2675
• 7 Bundred N, Kenemans P, Beckmann M et al. Effect of tibolone on breast cancer recurrence: Liberate trial bone sub-study.  Cancer Res. 2009;  69 (Suppl.) 79s
• 8 Familiari G, Caggiati A, Nottola S et al. Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin's disease.  Hum Reprod. 1993;  8 2080-2087
• 9 Gershenson D, Miller A, Champion V et al. Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: A Gynecologic Oncology Group study.  J Clin Oncol. 2007;  25 2792-2797
• 10 Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer – is it safe?), a randomised comparison: trial stopped.  Lancet. 2004;  363 453-455
• 11 Holmberg L, Iversen O, Rudenstam C et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.  J Natl Cancer Inst. 2008;  100 475-482
• 12 Kendall A, Dowsett M, Folkerd E et al. Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors.  Ann Oncol. 2006;  17 584-587
• 13 Kenemans P, Bundred N, Foidart J M et al. Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial.  Lancet Oncol. Published online January 23, 2009;  , Published online January 23, 2009
  
• 14 Lee S, Schover L, Partridge A et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.  J Clin Oncol. 2006;  24 1-11
• 15 Levgur M. Estrogen and combined hormone therapy for women after genital malignancies: A review.  J Reprod Med. 2004;  49 837-848
• 16 Mattle V, Behringer K, Engert A et al. Female fertility after cytotoxic therapy – protection of ovarian function during chemotherapy of malignant and non-malignant diseases.  Eur J Haematol. 2005;  66 (Suppl.) 77-82
• 17 Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction.  Hum Reprod Update. 2001;  7 535-543
• 18 Meirow D, Rabinovici J, Katz D et al. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate.  Cancer. 2006;  107 1634-1641
• 19 Morice P, Leblanc E, Rey A et al. Conservative treatment in epithelial ovarian cancer: results of a multicentre study of the GCCLCC and SFOG.  Hum Reprod. 2005;  20 1379-1385
• 20 Perez G, Knudson C, Leykin et al. Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction.  Nat Med. 1997;  3 1228-1232
• 21 Plante M, Renaud M, Gregoire J et al. Outcome of 81 pregnancies following radical trachelectomy for the treatment of early-stage cervical cancer.  Gynecol Oncol. 2008;  108 S32
• 22 Ploch E. Hormonal replacement therapy in patients after cervical cancer treatment.  Gynecol Oncol. 1987;  26 169-177
• 23 Randall T, Kurman R. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40.  Obstet Gynecol. 1997;  90 434-440
• 24 Schilder J, Thompson A, DePriest P et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy.  Gynecol Oncol. 2002;  87 1-7
• 25 Shepherd J, Spencer C, Herod J et al. Radical vaginal trachelectomy as a fertilty-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women.  Brit J Obstet Gynecol. 2006;  113 719-724
• 26 Sonmezer M, Oktay K. Fertility preservation in female patients.  Hum Reprod Update. 2004;  10 251-266
• 27 Stillman R, Schinfeld J, Schiff I et al. Ovarian failure in long-term survivors of childhood malignancy.  Am J Obstet Gynecol. 1981;  139 62-66
• 28 Tilly J. Oocyte apoptosis: prevention strategies, and implications for female aging and the menopause.  Ann Endocrinol. 2003;  64 82-84
• 29 Trinh X B, Tjalma W, Makar A et al. Use of levonorgestrel-releasing intrauterine system in breast cancer patients.  Fertil Steril. 2008;  91 17-22
• 30 Williams S, Blessing J, Liao S et al. Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: A trial of the Gynecologic Oncology group.  J Clin Oncol. 1994;  12 701-706
• 31 Ushijima K, Yahata H, Yoshikawa H et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women.  J Clin Oncol. 2007;  25 2798-2803
• 32 Zanetta G, Chiari S, Rota et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age.  Br J Obstet Gynaecol. 1997;  104 1030-1035
• 33 Zanetta G, Rota S, Chiari S et al. Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study.  J Clin Oncol. 2001;  19 2658-2664
• 34 Zanetta G, Bonazzi C, Cantu M et al. Survival and reproductive function after treatment of malignant germ cell ovarian tumors.  J Clin Oncol. 2001;  19 1015-1020
• 35 Zervomanolakis I, Hofer S, Mattle V et al. Kinderwunsch nach Chemotherapie – wissenschaftliche Perspektiven und klinische Anwendung.  J Gynäkol Endokrinol. 2008;  18 7-13