Geburtshilfe Frauenheilkd 2003; 63(3): R41-R64
DOI: 10.1055/s-2004-817985
GebFra-Refresher

Georg Thieme Verlag Stuttgart · New York

Der klinische Einsatz von GnRH-Analoga in der Gynäkologie

A. Rody1 , S. Kissler1 , R. R. Greb2 , M. Kaufmann1 , L. Kiesel2
  • 1Frankfurt
  • 2Münster
Further Information

Publication History

Publication Date:
02 April 2003 (online)

Die Herstellung synthetischer Gonadotropin-Releasing-Hormon-(GnRH-) Agonisten

GnRH-Agonisten steigern kurz die Gonadotropinauschüttung, bevor Hormonsynthese und -ausschüttung abfallen (desensitization).

wurde ursprünglich verfolgt, um über potentere Substanzen als natives GnRH für die Stimulationstherapie zu verfügen. Bei der Applikation fiel jedoch zunächst eine kurze Periode gesteigerter Gonadotropinausschüttung auf und erst nach längerer Gabe kam es zu einem Abfall der Hormonsynthese und -ausschüttung. Diese paradoxe Wirkungsweise, auch als „desensitization“ bezeichnet, wird für die Therapie zahlreicher sexualhormonabhängiger Erkrankungen genutzt. Durch die Einführung von GnRH-Antagonisten

GnRH-Antagonisten blockieren ohne Verzögerung die Gonadotropinausschüttung.

in die klinische Routine kann allerdings eine sofortige Blockade der Gonadotropinausschüttung erzielt werden. Der Einsatz von GnRH-Analoga stellt insbesondere in der Therapie hormonabhängiger gutartiger (z. B. Leiomyome des Uterus, dysfunktionelle Blutungsstörungen, Endometriose)

Hauptindikationen für GnRH-Analoga: hormonabhängige gutartige Tumoren, maligne Tumoren, COH.

und maligner Erkrankungen (Mamma-, Ovarial- und Endometriumkarzinom) eine wesentliche Ergänzung dar. Des Weiteren fanden die GnRH-Analoga durch die Inhibition der hypophysären Gonadotropinausschüttung bei der kontrollierten ovariellen Überstimulation (COH) Eingang in die Reproduktionsmedizin. Allerdings limitieren der Östrogenentzug mit den entsprechenden Begleitsymptomen und die Kosten den langfristigen Einsatz dieser Substanzen. Im Folgenden soll das Spektrum des therapeutischen Einsatzes synthetischer GnRH-Analoga bei gynäkologischen Erkrankungen dargestellt werden.

Literatur

  • 1 Kiesel L. Molecular mechanisms of gonadotrophin releasing hormone-stimulated gonadotrophin secretion.  Hum Reprod. 1993;  8 (Suppl. 2) 23-28
  • 2 Naor Z, Shacham S, Harris D, Seger R, Reiss N. Signal transduction of the gonadotropin releasing hormone (GnRH) receptor: cross talk of calcium, proteinkinase C (PKC) and arachidonic acid.  Cell Molec Neurobiol. 1996;  15 527-544
  • 3 Kiesel L, Kaufmann M, Haeseler P, Klinga K, von HoIst T, Schmidt W, Runnebaum B. GnRH-receptors in primary human breast cancer.  Geburtsh Frauenheilk. 1988;  48 420-424
  • 4 Latouche J, Crumeyrolle-Arias M, Jordan D. GnRH receptors in human granulosa cells: anatomical localization and characterization by autoradiographic study.  Endocrinology. 1989;  125 1739-1741
  • 5 Dong K W, Marcelin K, Hsu M I, Hoffman G, Roberts J L. Expression of gonadotropin-releasing hormone gene in human uterine endometrial tissue.  Mol Hum Reprod. 1998;  4 893-898
  • 6 Emons G, Pahwa G S, Brack C, Sturm R, Oberheuser F, Knuppen R. Gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata.  Eur J Cancer Clin Oncol. 1989;  25 215-221
  • 7 Lin Y, Kahn J A, Hillensjo T. Is there a difference in the function of granulosa-luteal cells in patients undergoing in-vitro fertilization either with gonadotropin-releasing hormone agonist or gonadotropin-releasing hormone antagonist?.  Hum Reprod. 1999;  14 885-888
  • 8 Duijkers I J, Klipping C, Willemsen W N, Krone D, Schneider E, Niebch G, Hermann R. Single and multiple dose pharmakokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers.  Hum Reprod. 1998;  13 2392-2398
  • 9 Barbieri R L. Hormone treatment of endometriosis: the estrogen threshold hypothesis.  Am J Obstet Gynecol. 1992;  166 740-745
  • 10 Surrey E S. Steridal or nonsteroidal “add-back” therapy: extending safety and efficacy of gonadotropin-releasing hormone agonist in the gynecologic patient.  Fertil Steril. 1995;  64 673-685
  • 11 Kiesel L, Schweppe K W, Sillem M, Siebzehnrubl E. Should add-back therapy for endometriosis be deferred for optimal results?.  Br J Obstet Gynaecol. 1996;  103 (Suppl 14) 15-17
  • 12 Franke H R, van de Weijer P H, Pennings T M, van der Mooren M J. Gonadotropin-releasing hormone agonist plus “add-back” hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial.  Fertil Steril. 2000;  74 534-539
  • 13 Stewart E A, Friedman A J. Steroidal treatment of myomas: preoperative and longterm medical therapy.  Semin Reprod Endocrinol. 1992;  10 344-357
  • 14 Friedman A J, Lobel S M, Rein M S, Barbieri R L. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis.  Am J Obstet Gynecol. 1990;  163 1114-1119
  • 15 Albertazzi P, Di Micco R, Zanardi E. Tibolone: a review.  Maturitas. 1998;  30 295-305
  • 16 Pierce S J, Gazvani M R, Farquharson R G. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up.  Fertil Steril. 2000;  74 964-968
  • 17 Bergquist C. Effects of nafarelin vs. danazol on lipids and Kalzium metabolism.  Am J Obstet Gynecol. 1990;  162 589-591
  • 18 Tonini G, Marinoni S, Forleo V, Rustica M. Local reactions to luteinizing hormone releasing hormone analogue therapy.  J Pediatr. 1995;  126 159
  • 19 Jay N, Mansfield M J, Blizzard R M, Crowley Jr W F, Schoenfeld D, Rhubin L, Boepple P A. Ovulation and menstrual function of adolescent girls with central prcocious puberty after therapy with gonadotropin-releasing hormone agonists.  J Clin Endocrinol Metab. 1992;  75 890-894
  • 20 Kiesel L, Bertges K, von Holst T R, Runnebaum B. Treatment of endometriosis.  Arch Gynecol Obstet. 1989;  245 937-940
  • 21 Lemay A, Maheux R, Huot C, Blanchet J, Faure N. Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis.  Am J Obstet Gynecol. 1988;  158 233-236
  • 22 Prentice A, Deary A J, Goldbeck-Wood S, Farquhar C, Smith S K. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Sys Rev 2000; 2: CD000346. 
  • 23 Hughes E, Fedorkow D, Collins J, Vandekerckhove P. Ovulation suppression for endometriosis. Cochrane Database Sys Rev 2000; 2: CD000155. 
  • 24 Thomas E J. The relevance of asymptomatic endometriosis.  Hum Reprod. 1996;  11 (Suppl. 3) 103-109
  • 25 Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell'Endometriosi.  Hum Reprod. 1999;  14 1332-1334
  • 26 Fedele L, Bianchi S, Zanconato G, Tozzi L, Raffaelli R. Gonadotropin-releasing hormone agonist treatment for endometriosis of the rectovaginal septum.  Am J Obstet Gynecol 2000. 2000;  183 1462-1467
  • 27 Schindler A E, Foertig P, Kienle E, Regidor P A. Early treatment of endometriosis with GnRH-agonists: impact on time to recurrence.  Eur J Obstet Gynecol Reprod Biol,. 2000;  93 123-125
  • 28 Letterie G S, Coddington C C, Winkel C A, Shawker T H, Loriaux D L, Collins L R. Efficacy of a gonadotropin-releasing hormone agonist in the treatment of uterine leiomyomata: long-term Follow-up.  Fertil Steril. 1989;  51 951-956
  • 29 Cheng Y M, Chou C Y, Huang S C, Lin H C. Oestrogen deficiency causes DANN damage in uterine leiomyoma cells: a possible mechanism for shrinkage of fibroids by GnRH agonists.  Br J Obstet Gynecol. 2001;  108 95-102
  • 30 Gokdeniz R, Ozen S, Mizrak B, Bazoglu N. GnRH agonist decreases endothelial nitric oxide synthase (eNOS) expression in leiomyoma.  Int J Gynecol Obstet. 2000;  70 347-352
  • 31 Kawaguchi D, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. Mitotic activity in uterine leiomyomas during the menstrual cycle.  Am J Obstet Gynecol. 1989;  160 637-641
  • 32 Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjoblom P, Norgren A, Lindblom B. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment.  J Clin Endocrinol Metab. 1998;  83 4092-4096
  • 33 Maruo T, Matsuo H, Smoto T, Shimomura Y, Kurachi O, Gao Z, Wang Y, Spitz I M, Johansson E. Effects of progesterone on uterine leiomyoma growth and apoptosis.  Steroids. 2000;  65 585-592
  • 34 Friedman A J, Barbieri R L, Doubilet P M, Fine C, Schiff I. A randomized, double-blind trial of a gonadotropin releasing hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri.  Fertil Steril. 1988;  49 404-409
  • 35 Stovall T G, Ling F W, Henry L C, Woodruff M R. A randomized trial evaluating leuprolide acetate before hysterectomy as treatment for leiomyomas.  Am J Obstet Gynecol. 1991;  164 1420-1423
  • 36 Felberbaum R E, Germer U, Ludwig M, Riethmuller-Winzen H, Heise S, Buttge I, Bauer O, Reissmann T, Engel J, Diedrich K. Treatment of uterine fibroids with a slow-release formulation of the gonadotrophin releasing hormone antagonist Cetrorelix.  Hum Reprod. 1998;  13 1660-1668
  • 37 Sculpher M, Thompson E, Brown J, Garry R. A cost effectiveness analysis of goserelin compared with danazol as endometrial thinning agents.  Br J Obstet Gynecol. 2000;  107 340-346
  • 38 Sowter Singla Lethaby M CAAA. Pre-operative endometrial thinning agents before hysteroscopic surgery for heavy menstrual bleeding. Cochrane Database Sys Rev 2000; 2: CD001124. 
  • 39 Weeks A D, Duffy S R, Walker J J. A double blind randomised trial of leuprorelin acetate prior to hysterectomy for dysfunctional uterine bleeding.  Br J Obstet Gynecol. 2000;  107 323-328
  • 40 Kurjac A, Kupesic S. Ovarian senescence and its significance on uterine and ovarian perfusion.  Fertil Steril. 1995;  64 532-537
  • 41 Grimbizis G, Tsalikis T, Tzioufa V, Kasapis M, Mantalenakis S. Regression of endometrial hyperplasia after treatment with the gonadotrophin-releasing hormone analogue triptorelin: a prospective study.  Hum Reprod. 1999;  14 479-484
  • 42 Early Breast Cancer Trialists' Collaborative Group . Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy.  Lancet. 1992;  399 1-15
  • 43 Paradiso A, Pezzetta A, Cellamare G, Schittulli F, Marzullo F, Reshkin S J. GnRH receptors in human breast cancer and its contiguous not-involved breast tissue.  J Endocrinol Invest. 2000;  23 90-96
  • 44 Jonat W, Kaufmann M, Blamey R W, Howell A, Collins J P, Coates A, Eiermann W, Janicke F, Njordenskold B, Forbes J F, Kolvenbag G JCM. A randomized study to compare the effect of the luteinizing hormone-releasing hormone (LH-RH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer.  Eur J Cancer. 1995;  31 A 137-142
  • 45 Klijn J G, Beex L V, Mauriac L, van Zijl J A, Veyret C, Wildiers J, Jassem J, Piccart M, Burghouts J, Becquart D, Seynaeve C, Mignolet F, Duchateau L. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cacner: a randomized study.  J Natl Cancer Inst. 2000;  92 903-911
  • 46 Roche H H, Kerbrat P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, Chapelle-Marcillac I, Bardonnet M. Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients with positive hormone-receptor. Proc Am Soc Clin Oncol 2000: abstract 279
  • 47 Kim J H, Park D C, Kim J W, Choi Y K, Lew Y O, Kim D H, Jung J K, Lim Y A, Namkoong S E. Antitumor effects of GnRH agonist in epithelial ovarian cancer.  Gynecol Oncol. 1999;  74 170-180
  • 48 Emons G, Schally A V. The use of luteinizing hormone releasing hormone agonists and antagonists in gynecological cancers.  Hum Reprod. 1994;  7 1364-1379
  • 49 Wang P H, Chao H T, Lee W L. Use of a long-acting gonadotropin-releasing hormone agonist for treatment of steroid cell tumors of the ovary.  Fertil Steril. 1998;  69 353-355
  • 50 Emons G, Schulz K D. Primary and salvage therapy with LH-RH analogues in ovarian cancer.  Recent Results Cancer Res. 2000;  153 83-94
  • 51 Hofstra L S, Mourits M J, de Vries E G, Mulder N H, Willemse P H. Combined treatment with goserelin and tamoxifen in patients with advanced chemotherapy resistant ovarian cancer.  Anticancer Res. 1999;  19 3627-3630
  • 52 Chatzaki E, Bax C M, Eidne K A, Anderson L, Grudzinskas J G, Gallagher C J. The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor.  Cancer Res. 1996;  56 2059-2065
  • 53 Covens A, Thomas G, Shaw P, Ackerman I, Osborne R, Lukka H, Carey M, Fraussen E, Rochie K. A phase II study of leuprolide in advanced/recurrent endometrial cancer.  Gynecol Oncol. 1997;  64 126-129
  • 54 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 a gonadotrophin-releasing hormone agonist parallel to chemotherapy.  Human Reproduction. 1996;  11 1620-1626
  • 55 Anderson R A, Kinniburgh D, Baird D T. Preliminary experience of the use of a gonadotrophin-releasing hormone antagonist in ovulation induction/in-viitro fertilization prior to cancer treatment.  Hum Reprod. 1999;  14 2665-2668
  • 56 Porter R N, Smith W, Craft I L, Abdulwahid N A, Jacobs H S. Induction of ovulation for in-vitro fertilization using Buserelin and gonadotropins.  Lancet. 1984;  2 1284-1285
  • 57 Garcia J E, Padilla S L, Bayati J, Baramki T A. Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization.  Fertil Steril. 1990;  53 302-305
  • 58 Tan S L, Kingsland C, Campbell S, Mills C, Bradfield J, Alexander N, Yovich J, Jacobs H S. The long protocol of administration of gonadotropin-releasing hormone agonist is superior to the short protocol for ovarian stimulation for in-vitro fertilization.  Fertil Steril. 1992;  57 810-814
  • 59 Dada T, Salha O, Baillie H S, Sharma V. A comparison of three gonadotropin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study.  Hum Reprod. 1999;  14 288-293
  • 60 MacDougall M J, Tan S L, Jacobs J S. In-vitro fertilization and the ovarian hyperstimulation syndrome.  Hum Reprod. 1992;  7 597-600
  • 61 Kim C H, Cho Y K, Mok J E. Simplified ultralong protocol of gonadotrophin releasing hormone agonist for ovulation induction with intrauterine insemination in patients with endometriosis.  Hum Reprod. 1996;  11 398-402
  • 62 Daya S. Gonadotropin releasing hormone agonist protocols for pituitary desensitation in in vitro fertilization and gamete intrafallopian transfer cycles. Cochrane Database Sys Rev 2000; 1: CD001299. 
  • 63 Ranieri D M, Phophong P, Khadum I, Meo F, Davis C, Serhal P. Simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue (F-G-test) allows effective drug regimen selection for IVF.  Hum Reprod. 2001;  16 673-675
  • 64 Check J H, Nazari A, Barnea E R, Weiss W, Vetter B H. The efficacy of short-term gonadotrophin-releasing hormone agonists versus human chorionic gonadotrophin to enable oocyte release in gonadotrophin stimulated cycles.  Hum Reprod. 1993;  8 568-571
  • 65 Hughes E, Collins J, Vandekerckhove P. Gonadotrophin-releasing hormone analogue as an adjunct to gonadotropin therapy for clomiphen-resistant polycystic ovarian syndrome. Cochrane Database Sys Rev 2000; 2: CD000097. 
  • 66 Ludwig M, Felberbaum E R, Diedrich K, Hamm W, Riethmueller-Winzen H, Ulrich H. Cetrorelix im Mehrfachgabe-Protokoll zur ovariellen Stimulation bei der IVF.  Reproduktionsmedizin. 2000;  16 390-399
  • 67 Klingmuller D, Diedrich K, Sommer L. Effects of the GnRH antagonist Cetrorelix in normal women.  Gynecol Endocrinol. 1993;  7 2
  • 68 Christin-Maitre S, Olivennes F, Dubourdieu S, Chabbert-Buffet N, Charbonnel B, Frydman R P, Bouchard P. Effect of GnRH antaggonist during the LH surge in normal, women and during controlled ovarian hyperstimulation.  Clin Endocrinol. 2000;  52 721-726
  • 69 Olivennes F, Belaisch-Allart J, Emperaire J-C, Dechaud H, Alvarez S, Moreau L, Nicollet B, Zorn J R, Bouchard P, Frydman R. Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin).  Fertil Steril. 2000;  73 314-320
  • 70 Mannaerts B, Gordon K. Embryo implantation and GnRH antagonists: GnRH antagonists do not activate the GnRH receptor.  Hum Reprod. 2000;  15 1882-1883
  • 71 Hernandez E R. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists.  Hum Reprod. 2000;  15 1211-1216
  • 72 Mehta R H, Anand Kumar T C. Can GnRH agonists act directly on the ovary and contribute to cyst formation.  Hum Reprod. 2000;  15 505-507
  • 73 von Minckwitz G, Kaufmann M. New endocrine approaches in the treatment of brest cancer.  Biomed Pharmacother. 1998;  52 122-132
  • 74 Kaufmann M, Jonat W, Kleeberg U, Eiermann W. Goserelin, a depot GnRH-agonist in the treatment of premenopausal patients with metastatic breast cancer. German Zoladex Trial Group.  J Clin Oncol. 1989;  7 1113-1119
  • 75 Kaufmann M, von Minckwitz G. The emerging role of hormonal ablation as adjuvant therapy in node positive and node negative pre-/perimenopausal patients.  The Breast. 2001;  10 (Suppl. ) 123-129
  • 76 Jakesz R, Hausmaninger H, Samonigg H. Comparison of adjuvant therapy with tamoxifen and goserelin versus CMF in premenopausal stage I and II hormone-responsive breast cancer patients: four year results of ABCSG trial 5.  Proc Am Soc Clin Oncol. 1999;  18 67a
  • 77 Boccardo F, Rubagotti A, Amoroso D. Cyclophosphamide, methotrexate and fluoruracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: result of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial.  J Clin Oncol. 2000;  18 2718-2727