GnRH Agonists, Antagonists, and Assisted Conception

André C. D. van Loenen; Judith A. F. Huirne; Roel Schats; Peter G. A. Hompes; Cornelis B. Lambalk

doi:10.1055/s-2002-36713

Seminars in Reproductive Medicine, Inhaltsverzeichnis

Semin Reprod Med 2002; 20(4): 349-364
DOI: 10.1055/s-2002-36713

GnRH Agonists, Antagonists, and Assisted Conception

André C.D. van Loenen, Judith A.F. Huirne, Roel Schats, Peter G.A. Hompes, Cornelis B. Lambalk

Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Vrije Universiteit Medical Centre (VUMC), Amsterdam, The Netherlands

Abstract

ABSTRACT

Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) induces both follicle-stimulating hormone and luteinizing hormone (LH). Blockade of pituitary gonadotropin secretion occurs upon desensitization when a continuous GnRH stimulus is provided by means an agonist or when the pituitary receptors are occupied with a competitive antagonist. The most common indication for blockade of pituitary gonadotropin secretion is with assisted reproduction treatment (ART) where it prevents premature luteinization. Originally by lack of clinically available GnRH antagonist, prolonged daily injection of agonist with its desensitizing effect was introduced for this purpose. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge. This review provides an overview of the use of GnRH agonists and antagonists in assisted reproduction.

KEYWORD

GnRH - agonist - antagonist - assisted reproduction - IVF - IUI

Volltext

Referenzen

REFERENCES

1 Edwards R G. The history of assisted human conception with especial reference to endocrinology. Exp Clin Endocrinol Diabetes . 1996; 104 183-204
2 Janssens R M, Lambalk C B, Vermeiden J P. Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study. Hum Reprod . 2000; 15 2333-2340
3 Templeton A, Morris J K. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med . 1998; 339 573-577
4 Porter R N, Smith W, Craft I L, Abdulwahid N A, Jacobs H S. Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet . 1984; 2 1284-1285
5 Schally A V, Nair R M, Redding T W, Arimura A. Isolation of the luteinizing hormone and follicle-stimulating hormone-releasing hormone from porcine hypothalami. J Biol Chem . 1971; 246 7230-7236
6 Amos M, Burgus R, Blackwell R, Vale W, Fellows R, Guillemin R. Purification, amino acid composition and N-terminus of the hypothalamic luteinizing hormone releasing factor (LRF) of bovine origin. Biochem Biophys Res Commun . 1971; 44 205-210
7 Sealfon S C, Weinstein H, Millar R P. Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr Rev . 1997; 18 180-205
8 Yahalom D, Chen A, Ben Aroya N. The gonadotropin-releasing hormone family of neuropeptides in the brain of human, bovine and rat: identification of a third isoform. FEBS Lett . 1999; 463 289-294
9 Yang-Feng T L, Seeburg P H, Francke U. Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2-p21). Somat Cell Mol Genet . 1986; 12 95-100
10 White R B, Eisen J A, Kasten T L, Fernald R D. Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci U S A . 1998; 95 305-309
11 Probst J C, Skutella T, Muller-Schmid A, Jirikowski G F, Hoffmann W. Molecular and cellular analysis of rP1.B in the rat hypothalamus: in situ hybridization and immunohistochemistry of a new P-domain neuropeptide. Brain Res Mol Brain Res . 1995; 33 269-276
12 Kottler M L, Lorenzo F, Bergametti F, Commercon P, Souchier C, Counis R. Subregional mapping of the human gonadotropin-releasing hormone receptor (GnRH-R) gene to 4q between the markers D4S392 and D4S409. Hum Genet . 1995; 96 477-480
13 Millar R, Lowe S, Conklin D. A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc Natl Acad Sci U S A . 2001; 98 9636-9641
14 Neill J D, Duck L W, Sellers J C, Musgrove L C. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun . 2001; 282 1012-1018
15 Janssens R M, Brus L, Cahill D J, Huirne J A, Schoemaker J, Lambalk C B. Direct ovarian effects and safety aspects of GnRH agonists and antagonists. Hum Reprod Update . 2000; 6 505-518
16 Stojilkovic S S, Reinhart J, Catt K J. Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev . 1994; 15 462-499
17 Kaiser U B, Conn P M, Chin W W. Studies of gonadotropin-releasing hormone (GnRH) action using GnRH receptor-expressing pituitary cell lines. Endocr Rev . 1997; 18 46-70
18 Conn P M, Crowley Jr F W. Gonadotropin-releasing hormone and its analogs. Annu Rev Med . 1994; 45 391-405
19 Karten M J, Rivier J E. Gonadotropin-releasing hormone analog design-structure-function studies toward the development of agonists and antagonists: rationale and perspective. Endocr Rev . 1986; 7 44-66
20 Huirne J AF, Lambalk C B. Gonadotropin-releasing-hormone-receptor antagonists. Lancet . 2001; 358 1793-1803
21 Schally A V. Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides . 1999; 20 1247-1262
22 Bajusz S, Kovacs M, Gazdag M. Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects. Proc Natl Acad Sci U S A . 1988; 85 1637-1641
23 Ljungqvist A, Feng D M, Hook W, Shen Z X, Bowers C, Folkers K. Antide and related antagonists of luteinizing hormone release with long action and oral activity. Proc Natl Acad Sci U S A . 1988; 85 8236-8240
24 Rivier J, Porter J, Hoeger C. Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine, -lysine, or -p-aminophenylalanine residues at positions 5 and 6. J Med Chem . 1992; 35 4270-4278
25 Nestor Jr J J, Tahilramani R, Ho T L, Goodpasture J C, Vickery B H, Ferrandon P. Potent gonadotropin releasing hormone antagonists with low histamine-releasing activity. J Med Chem . 1992; 35 3942-3948
26 Garnick M B, Campion M. Abarelix Depot, a GnRH antagonist, v LHRH superagonists in prostate cancer: differential effects on follicle-stimulating hormone. Abarelix Depot study group. Mol Urol . 2000; 4 275-277
27 Cook T, Sheridan W P. Development of GnRH antagonists for prostate cancer: new approaches to treatment. Oncologist . 2000; 5 162-168
28 Brus L, Lambalk C B, de Koning J, Helder M N, Janssens R M, Schoemaker J. Specific gonadotrophin-releasing hormone analogue binding predominantly in human luteinized follicular aspirates and not in human pre-ovulatory follicles. Hum Reprod . 1997; 12 769-773
29 Raga F, Casan E M, Kruessel J, Wen Y, Bonilla-Musoles F, Polan M L. The role of gonadotropin-releasing hormone in murine preimplantation embryonic development. Endocrinology . 1999; 140 3705-3712
30 Lahat E, Raziel A, Friedler S, Schieber-Kazir M, Ron-El R. Long-term follow-up of children born after inadvertent administration of a gonadotrophin-releasing hormone agonist in early pregnancy. Hum Reprod . 1999; 14 2656-2660
31 The Ganirelix Dose-Finding Study Group. A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum Reprod . 1990; 13 3023-3031
32 Kol S, Lightman A, Hillensjo T. High doses of gonadotrophin-releasing hormone antagonist in in-vitro fertilization cycles do not adversely affect the outcome of subsequent freeze-thaw cycles. Hum Reprod . 1999; 14 2242-2244
33 Anik S T, McRae G, Nerenberg C. Nasal absorption of nafarelin acetate, the decapeptide [D-Nal 6)]LHRH, in rhesus monkeys I. J Pharm Sci . 1984; 73 684-685
34 Holland F J, Fishman L, Costigan D C, Luna L, Leeder S. Pharmacokinetic characteristics of the gonadotropin-releasing hormone analog D-Ser(TBU)-6EA-10 luteinizing hormone-releasing hormone (buserelin) after subcutaneous and intranasal administration in children with central precocious puberty. J Clin Endocrinol Metab . 1986; 63 1065-1070
35 Broekmans F J, Bernardus R E, Berkhout G, Schoemaker J. Pituitary and ovarian suppression after early follicular and mid-luteal administration of a LHRH agonist in a depot formulation: decapeptyl CR. Gynecol Endocrinol . 1992; 6 153-161
36 Porcu E, Dal Prato L, Seracchioli R, Fabbri R, Longhi M, Flamigni C. Comparison between depot and standard release triptoreline in in vitro fertilization: pituitary sensitivity, luteal function, pregnancy outcome, and perinatal results. Fertil Steril . 1994; 62 126-132
37 Porcu E, Filicori M, Dal Prato L. Comparison between depot leuprorelin and daily buserelin in IVF. J Assist Reprod Genet . 1995; 12 15-19
38 Devreker F, Govaerts I, Bertrand E, van den M B, Gervy C, Englert Y. The long-acting gonadotropin-releasing hormone analogues impaired the implantation rate. Fertil Steril . 1996; 65 122-126
39 Fujii S, Sato S, Fukui A, Kimura H, Kasai G, Saito Y. Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF. Hum Reprod . 2001; 16 1671-1675
40 Oppenheim D S, Bikkal H, Crowley Jr F W, Klibanski A. Effects of chronic GnRH analogue administration on gonadotrophin and alpha-subunit secretion in post-menopausal women. Clin Endocrinol (Oxf) . 1992; 36 559-564
41 Winslow K L, Gordon K, Williams R F, Hodgen G D. Interval required for gonadotropin-releasing hormone-agonist-induced down regulation of the pituitary in cynomolgus monkeys and duration of the refractory state. Fertil Steril . 1992; 58 1209-1214
42 Sungurtekin U, Jansen R P. Profound luteinizing hormone suppression after stopping the gonadotropin-releasing hormone-agonist leuprolide acetate. Fertil Steril . 1995; 63 663-665
43 Fujii S, Sagara M, Kudo H, Kagiya A, Sato S, Saito Y. A prospective randomized comparison between long and discontinuous-long protocols of gonadotropin-releasing hormone agonist for in vitro fertilization. Fertil Steril . 1997; 67 1166-1168
44 Klein K O, Barnes K M, Jones J V, Feuillan P P, Cutler Jr B G. Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab . 2001; 86 4711-4716
45 Oerter K E, Manasco P, Barnes K M, Jones J, Hill S, Cutler Jr B G. Adult height in precocious puberty after long-term treatment with deslorelin. J Clin Endocrinol Metab . 1991; 73 1235-1240
46 Palmert M R, Mansfield M J, Crowley Jr F W, Crigler Jr F J, Crawford J D, Boepple P A. Is obesity an outcome of gonadotropin-releasing hormone agonist administration?. <~>Analysis of growth and body composition in 110 patients with central precocious puberty. J Clin Endocrinol Metab . 1999; 84 4480-4488
47 Schlegel P N, Kuzma P, Frick J. Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin. Urology . 2001; 58 578-582
48 Chertin B, Spitz I M, Lindenberg T. An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer. J Urol . 2000; 163 838-844
49 Spitz I M, Chertin B, Lindenberg T, Farkas A. Long-acting gonadotropin-releasing hormone implant to maintain medical castration for two years in men with prostate cancer [letter]. N Engl J Med . 1999; 340 1439
50 Gonen Y, Dirnfeld M, Goldman S, Koifman M, Abramovici H. The use of long-acting gonadotropin-releasing hormone agonist (GnRH-a; decapeptyl) and gonadotropins versus short-acting GnRH-a (buserelin) and gonadotropins before and during ovarian stimulation for in vitro fertilization (IVF). J In Vitro Fert Embryo Transf . 1991; 8 254-259
51 Balasch J, Jove I C, Moreno V, Civico S, Puerto B, Vanrell J A. The comparison of two gonadotropin-releasing hormone agonists in an in vitro fertilization program. Fertil Steril . 1992; 58 991-994
52 Penzias A S, Shamma F N, Gutmann J N, Jones E E, DeCherney A H, Lavy G. Nafarelin versus leuprolide in ovulation induction for in vitro fertilization: a randomized clinical trial. Obstet Gynecol . 1992; 79 739-742
53 Tapanainen J, Hovatta O, Juntunen K. Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study. Hum Reprod . 1993; 8 2052-2055
54 Dantas Z N, Vicino M, Balmaceda J P, Asch R H, Stone S C. Comparison between nafarelin and leuprolide acetate for in vitro fertilization: preliminary clinical study. Fertil Steril . 1994; 61 705-708
55 Goldman J A, Dicker D, Feldberg D, Ashkenazi J, Voliowich I. A prospective randomized comparison of two gonadotrophin-releasing hormone agonists, nafarelin acetate and buserelin acetate, in in-vitro fertilization-embryo transfer. Hum Reprod . 1994; 9 226-228
56 Lockwood G M, Pinkerton S M, Barlow D H. A prospective randomized single-blind comparative trial of nafarelin acetate with buserelin in long-protocol gonadotrophin-releasing hormone analogue controlled in-vitro fertilization cycles. Hum Reprod . 1995; 10 293-298
57 Oyesanya O A, Teo S K, Quah E, Abdurazak N, Lee F Y, Cheng W C. Pituitary down-regulation prior to in-vitro fertilization and embryo transfer: a comparison between a single dose of Zoladex depot and multiple daily doses of Suprefact. Hum Reprod . 1995; 10 1042-1044
58 Tanos V, Friedler S, Shushan A, Strauss N, Hetsroni I, Lewin A. Comparison between nafarelin acetate and D-Trp6-LHRH for temporary pituitary suppression in in vitro fertilization (IVF) patients: a prospective crossover study. J Assist Reprod Genet . 1995; 12 715-719
59 Avrech O M, Goldman G A, Pinkas H. Intranasal nafarelin versus buserelin (short protocol) for controlled ovarian hyperstimulation before in vitro fertilization: a prospective clinical trial. Gynecol Endocrinol . 1996; 10 165-170
60 Corson S L, Gutmann J N, Batzer F R, Gocial B. A double-blind comparison of nafarelin and leuprolide acetate for down-regulation in IVF cycles. Int J Fertil Menopausal Stud . 1996; 41 446-449
61 Westergaard L G, Erb K, Laursen S B, Rex S, Rasmussen P E. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotropic women down-regulated with a gonadotropin-releasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril . 2001; 76 543-549
62 Wong J M, Forrest K A, Snabes S Z, Zhao S Z, Gersh G E, Kennedy S H. Efficacy of nafarelin in assisted reproductive technology: a meta-analysis. Hum Reprod Update . 2001; 7 92-101
63 Zorn J R, Boyer P, Guichard A. Never on a Sunday: programming for IVF-ET and GIFT. Lancet . 1987; 1 385-386
64 Pellicer A, Simon C, Miro F. Ovarian response and outcome of in-vitro fertilization in patients treated with gonadotrophin-releasing hormone analogues in different phases of the menstrual cycle. Hum Reprod . 1989; 4 285-289
65 Daya S. Gonadotrophin-releasing hormone agonist protocols for pituitary desensitization in in vitro fertilization and gamete intrafallopian transfer cycles (Cochrane Review). In: The Cochrane Library, Issue 1 Oxford: Update Software; 2000
66 Kondaveeti-Gordon U, Harrison R F, Barry-Kinsella C, Gordon A C, Drudy L, Cottell E. A randomized prospective study of early follicular or midluteal initiation of long protocol gonadotropin-releasing hormone in an in vitro fertilization program. Fertil Steril . 1996; 66 582-586
67 Ron-El R, Herman A, Golan A, van der Ven H, Caspi E, Diedrich K. The comparison of early follicular and midluteal administration of long-acting gonadotropin-releasing hormone agonist. Fertil Steril . 1990; 54 233-237
68 San Roman A G, Surrey E S, Judd H L, Kerin J F. A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization. Fertil Steril . 1992; 58 744-749
69 Chang S Y, Lee C L, Wang M L. No detrimental effects in delaying initiation of gonadotropin administration after pituitary desensitization with gonadotropin-releasing hormone agonist. Fertil Steril . 1993; 59 183-186
70 Abdalla H I, Baber R J, Leonard T. Timed oocyte collection in an assisted conception programme using GnRH analogue. Hum Reprod . 1989; 4 927-930
71 Dimitry E S, Oskarsson T, Conaghan J, Margara R, Winston R M. Beneficial effects of a 24 h delay in human chorionic gonadotrophin administration during in-vitro fertilization treatment cycles. Hum Reprod . 1991; 6 944-946
72 Tan S L, Brinsden P. The use of luteinising hormone releasing hormone agonists for ovarian stimulation in assisted reproductive technology. Ann Acad Med Singapore . 1992; 21 504-509
73 Tan S L. Luteinizing hormone-releasing hormone agonists for ovarian stimulation in assisted reproduction. Curr Opin Obstet Gynecol . 1994; 6 166-172
74 Gonen Y, Jacobson W, Casper R F. Gonadotropin suppression with oral contraceptives before in vitro fertilization. Fertil Steril . 1990; 53 282-287
75 Kemeter P, Feichtinger W. Experience with a new fixed-stimulation protocol without hormone determinations for programmed oocyte retrieval for in-vitro fertilization. Hum Reprod . 1989; 4 53-58
76 Patton P E, Burry K A, Wolf D P, Kiessling A A, Craemer M J. The use of oral contraceptives to regulate oocyte retrieval. Fertil Steril . 1988; 49 716-718
77 Templeton A, van Look P, Lumsden M A. The recovery of pre-ovulatory oocytes using a fixed schedule of ovulation induction and follicle aspiration. Br J Obstet Gynaecol . 1984; 91 148-154
78 Jenkins J M. Cyst formation. Hum Reprod . 1995; 10 3079-3080
79 Keltz M D, Jones E E, Duleba A J, Polcz T, Kennedy K, Olive D L. Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome. Fertil Steril . 1995; 64 568-572
80 Feldberg D, Ashkenazi J, Dicker D. Ovarian cyst formation: a complication of gonadotropin-releasing hormone agonist therapy. Fertil Steril . 1989; 51 42-45
81 Biljan M M, Mahutte N G, Dean N, Hemmings R, Bissonnette F, Tan S L. Pretreatment with an oral contraceptive is effective in reducing the incidence of functional ovarian cyst formation during pituitary suppression by gonadotropin-releasing hormone analogues. J Assist Reprod Genet . 1998; 15 599-604
82 Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs R P. An alternate approach to controlled ovarian hyperstimulation in "poor responders": pretreatment with a gonadotropin-releasing hormone analog. Fertil Steril . 1988; 49 90-95
83 Damario M A, Barmat L, Liu H C, Davis O K, Rosenwaks Z. Dual suppression with oral contraceptives and gonadotrophin releasing-hormone agonists improves in-vitro fertilization outcome in high responder patients. Hum Reprod . 1997; 12 2359-2365
84 Barriere P, Lopes P, Boiffard J P. Use of GnRH analogues in ovulation induction for in vitro fertilization: benefit of a short administration regimen. J In Vitro Fert Embryo Transf . 1987; 4 64-65
85 Smitz J, Bollen N, Camus M, Devroey P, Wisanto A, Van Steirteghem C A. Short-term use of buserelin in combination with human menopausal gonadotrophins for ovarian stimulation for in-vitro fertilization in endocrinologically normal women. Hum Reprod . 1990; 5 157-162
86 Acharya U, Irvine S, Hamilton M, Templeton A. Prospective study of short and ultrashort regimens of gonadotropin-releasing hormone agonist in an in vitro fertilization program. Fertil Steril . 1992; 58 1169-1173
87 Howles C M, Macnamee M C, Edwards R G. Short term use of an LHRH agonist to treat poor responders entering an in-vitro fertilization programme. Hum Reprod . 1987; 2 655-656
88 Macnamee M C, Howles C M, Edwards R G, Taylor P J, Elder K T. Short-term luteinizing hormone-releasing hormone agonist treatment: prospective trial of a novel ovarian stimulation regimen for in vitro fertilization. Fertil Steril . 1989; 52 264-269
89 Martikainen H, Ronnberg L, Tapanainen J, Puistola U, Orava M, Kauppila A. Endocrine responses to gonadotrophins after LHRH agonist administration on cycle days 1-4: prevention of premature luteinization. Hum Reprod . 1990; 5 246-249
90 Sharma V, Williams J, Collins W, Riddle A, Mason B, Whitehead M. The sequential use of a luteinizing hormone-releasing hormone (LH-RH) agonist and human menopausal gonadotropins to stimulate folliculogenesis in patients with resistant ovaries. J In Vitro Fert Embryo Transf . 1988; 5 38-42
91 Corson S L, Batzer F R, Gocial B, Eisenberg E, Huppert L C, Nelson J R. Leuprolide acetate-prepared in vitro fertilization-gamete intrafallopian transfer cycles: efficacy versus controls and cost analysis. Fertil Steril . 1992; 57 601-605
92 de Ziegler D, Cedars M I, Randle D, Lu J K, Judd H L, Meldrum D R. Suppression of the ovary using a gonadotropin releasing-hormone agonist prior to stimulation for oocyte retrieval. Fertil Steril . 1987; 48 807-810
93 Pantos K, Meimeth-Damianaki T, Vaxevanoglou T, Kapetanakis E. Prospective study of a modified gonadotropin-releasing hormone agonist long protocol in an in vitro fertilization program. Fertil Steril . 1994; 61 709-713
94 Smitz J, Erard P, Camus M. Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol. Hum Reprod . 1992; 7 1225-1229
95 Smitz J, Van Den E A, Bollen N. The effect of gonadotrophin-releasing hormone (GnRH) agonist in the follicular phase on in-vitro fertilization outcome in normo-ovulatory women. Hum Reprod . 1992; 7 1098-1102
96 Hazout A, de Ziegler D, Cornel C, Fernandez H, Lelaidier C, Frydman R. Comparison of short 7-day and prolonged treatment with gonadotropin-releasing hormone agonist desensitization for controlled ovarian hyperstimulation. Fertil Steril . 1993; 59 596-600
97 Yang T S, Tsan S H, Wang B C, Chang S P, Ng H T. The evaluation of a new 7-day gonadotropin-releasing hormone agonist protocol in the controlled ovarian hyperstimulation for in vitro fertilization. J Obstet Gynaecol Res . 1996; 22 133-137
98 Cedrin-Durnerin I, Bidart J M, Robert P, Wolf J P, Uzan M, Hugues J N. Consequences on gonadotrophin secretion of an early discontinuation of gonadotrophin-releasing hormone agonist administration in short-term protocol for in-vitro fertilization. Hum Reprod . 2000; 15 1009-1014
99 Tolis G, Ackman D, Stellos A. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Proc Natl Acad Sci U S A . 1982; 79 1658-1662
100 Schoemaker J, Scheele F, Broekmans F, Janssens R M. GnRH agonists: to dose or to overdose?. In: Shoham Z, Howles CM, Jacobs HS, eds. Female Infertility Therapy: Current Practice London: Martin Dunitz 1999: 169-170
101 Janssens R M, Vermeiden J P, Lambalk C B, Schats R, Schoemaker J. Gonadotrophin-releasing hormone agonist dose-dependency of pituitary desensitization during controlled ovarian hyperstimulation in IVF. Hum Reprod . 1998; 13 2386-2391
102 Lefebvre G. Comparison of two dosages of nafarelin nasal solution with hMG in a short protocol of ovarian stimulation for in vitro fertilization. Nafarelin Recent Advances. London: Parthenon Publishing 1990: 15-21
103 Polson D W, MacLachlan V, Krapez J A, Wood C, Healy D L. A controlled study of gonadotropin-releasing hormone agonist (buserelin acetate) for folliculogenesis in routine in vitro fertilization patients. Fertil Steril . 1991; 56 509-514
104 Simon A, Benshushan A, Shushan A. A comparison between a standard and reduced dose of D-Trp-6-luteinizing hormone-releasing hormone administered after pituitary suppression for in-vitro fertilization. Hum Reprod . 1994; 9 1813-1817
105 Sandow J, Donnez J. Clinical pharmakinetics of LHRH analogues. In: Brosens I, Jacobs HS, Runnebaum B, eds. LHRH Analogues in Gynaecology London: CRC Press-Parthenon Publishers 2002: 17-31
106 Elgendy M, Afnan M, Holder R. Reducing the dose of gonadotrophin-releasing hormone agonist on starting ovarian stimulation: effect on ovarian response and in-vitro fertilization outcome. Hum Reprod . 1998; 13 2382-2385
107 Takeuchi S, Minoura H, Shibahara T, Tsuiki Y, Noritaka F, Toyoda N. A prospective randomized comparison of routine buserelin acetate and a decreasing dosage of nafarelin acetate with a low-dose gonadotropin-releasing hormone agonist protocol for in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril . 2001; 76 532-537
108 Feldberg D, Farhi J, Ashkenazi J, Dicker D, Shalev J, Ben Rafael Z. Minidose gonadotropin-releasing hormone agonist is the treatment of choice in poor responders with high follicle-stimulating hormone levels. Fertil Steril . 1994; 62 343-346
109 Olivennes F, Righini C, Fanchin R. A protocol using a low dose of gonadotrophin-releasing hormone agonist might be the best protocol for patients with high follicle-stimulating hormone concentrations on day 3. Hum Reprod . 1996; 11 1169-1172
110 Fleming R, Black W P, Coutts J R. Effects of LH suppression in polycystic ovary syndrome. Clin Endocrinol (Oxf) . 1985; 23 683-688
111 Dodson W C, Hughes C L, Whitesides D B, Haney A F. The effect of leuprolide acetate on ovulation induction with human menopausal gonadotropins in polycystic ovary syndrome. J Clin Endocrinol Metab . 1987; 65 95-100
112 Homburg R, Kilborn J, West C, Jacobs H S. Treatment with pulsatile luteinizing hormone-releasing hormone modulates folliculogenesis in response to ovarian stimulation with exogenous gonadotropins in patients with polycystic ovaries. Fertil Steril . 1990; 54 737-739
113 Weise H C, Fiedler K, Kato K. Buserelin suppression of endogenous gonadotropin secretion in infertile women with ovarian feedback disorders given human menopausal/human chorionic gonadotropin treatment. Fertil Steril . 1988; 49 399-403
114 Buckler H M, Healy D L, Burger H G. Does gonadotropin suppression result in follicular development in premature ovarian failure?. Gynecol Endocrinol . 1993; 7 123-128
115 Scheele F, Hompes P G, van der M M, Schoute E, Schoemaker J. The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome. Hum Reprod . 1993; 8 699-704
116 Vegetti W, Testa G, Ragni G, Parazzini F, Crosignani P G. Ovarian stimulation with low-dose pure follicle-stimulating hormone in polycystic ovarian syndrome anovulatory patients: effect of long-term pretreatment with gonadotrophin-releasing hormone analogue. Gynecol Obstet Invest . 1998; 45 186-189
117 Eshel A, Abdulwahid N A, Armar N A, Adams J M, Jacobs H S. Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome. Fertil Steril . 1988; 49 956-960
118 Filicori M, Flamigni C, Dellai P. Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles. J Clin Endocrinol Metab . 1994; 79 1215-1220
119 Shoham Z, Homburg R, Jacobs H S. Induction of ovulation with pulsatile GnRH. Baillieres Clin Obstet Gynaecol . 1990; 4 589-608
120 Hughes E, Collins J, Vandekerckhove P. Gonadothrophin-releasing hormone analogue as an adjunct to gonadotropin therapy for clomiphene-resistant polycystic ovarian syndrome (Cochrane review). In: The Cochrane Library, Issue 4 Oxford: Update Software; 2002
121 Dor J, Shulman A, Levran D, Ben Rafael Z, Rudak E, Mashiach S. The treatment of patients with polycystic ovarian syndrome by in-vitro fertilization and embryo transfer: a comparison of results with those of patients with tubal infertility. Hum Reprod . 1990; 5 816-818
122 Homburg R, Berkowitz D, Levy T, Feldberg D, Ashkenazi J, Ben Rafael Z. In vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome. Fertil Steril . 1993; 60 858-863
123 MacDougall M J, Tan S L, Balen A, Jacobs H S. A controlled study comparing patients with and without polycystic ovaries undergoing in-vitro fertilization. Hum Reprod . 1993; 8 233-237
124 Fleming R, Coutts J R. LHRH analogues for ovulation induction, with particular reference to polycystic ovary syndrome. Baillieres Clin Obstet Gynaecol . 1988; 2 677-687
125 Abdalla H I, Ahuja K K, Leonard T, Morris N N, Honour J W, Jacobs H S. Comparative trial of luteinizing hormone-releasing hormone analog/human menopausal gonadotropin and clomiphene citrate/human menopausal gonadotropin in an assisted conception program. Fertil Steril . 1990; 53 473-478
126 Jacobs H S. Polycystic ovaries and polycystic ovary syndrome. Gynecol Endocrinol . 1987; 1 113-131
127 Ben Rafael Z, Bider D, Dan U, Zolti M, Levran D, Mashiach S. Combined gonadotropin releasing hormone agonist/human menopausal gonadotropin therapy (GnRH-a/hMG) in normal, high, and poor responders to hMG. J In Vitro Fert Embryo Transf . 1991; 8 33-36
128 Jenkins J M, Davies D W, Devonport H. Comparison of "poor" responders with "good" responders using a standard buserelin/human menopausal gonadotrophin regime for in-vitro fertilization. Hum Reprod . 1991; 6 918-921
129 Land J A, Yarmolinskaya M I, Dumoulin J C, Evers J L. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril . 1996; 65 961-965
130 Muasher S J. Treatment of low responders. J Assist Reprod Genet . 1993; 10 112-114
131 Padilla S L, Dugan K, Maruschak V, Shalika S, Smith R D. Use of the flare-up protocol with high dose human follicle stimulating hormone and human menopausal gonadotropins for in vitro fertilization in poor responders. Fertil Steril . 1996; 65 796-799
132 Tasdemir M, Tasdemir I, Kodama H, Fukuda J, Tanaka T. Short protocol of gonadotropin releasing hormone agonist administration gave better results in long protocol poor-responders in IVF-ET. J Obstet Gynaecol Res . 1996; 22 73-77
133 Yang J H, Wu M Y, Chao K H, Chen S U, Ho H N, Yang Y S. Long GnRH-agonist protocol in an IVF program: is it appropriate for women with normal FSH levels and high FSH/LH ratios?. J Reprod Med . 1997; 42 663-668
134 Gelety T J, Pearlstone A C, Surrey E S. Short-term endocrine response to gonadotropin-releasing hormone agonist initiated in the early follicular, midluteal, or late luteal phase in normally cycling women. Fertil Steril . 1995; 64 1074-1080
135 Loumaye E, Vankrieken L, Depreester S, Psalti I, De Cooman S, Thomas K. Hormonal changes induced by short-term administration of gonadotropin-releasing hormone agonist during ovarian hyperstimulation for in vitro fertilization and their consequences for embryo development. Fertil Steril . 1989; 51 105-111
136 Fasouliotis S J, Simon A, Laufer N. Evaluation and treatment of low responders in assisted reproductive technology: a challenge to meet. J Assist Reprod Genet . 2000; 17 357-373
137 Scott R T, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril . 1994; 61 880-885
138 Fisch B, Royburt M, Pinkas H. Augmentation of low ovarian response to superovulation before in vitro fertilization following priming with contraceptive pills. Isr J Med Sci . 1996; 32 1172-1176
139 Abramov Y, Elchalal U, Schenker J G. Severe OHSS-an "epidemic" of severe OHSS: a price we have to pay?. Hum Reprod . 1999; 14 2181-2183
140 Forman R G, Frydman R, Egan D, Ross C, Barlow D H. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril . 1990; 53 502-509
141 Golan A, Ron-El R, Herman A, Weinraub Z, Soffer Y, Caspi E. Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization. Fertil Steril . 1988; 50 912-916
142 Maroulis G B, Emery M, Verkauf B S, Saphier A, Bernhisel M, Yeko T R. Prospective randomized study of human menotropin versus a follicular and a luteal phase gonadotropin-releasing hormone analog-human menotropin stimulation protocols for in vitro fertilization. Fertil Steril . 1991; 55 1157-1164
143 Navot D, Bergh P A, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril . 1992; 58 249-261
144 Gerris J, De Vits A, Joostens M, Van Royen E. Triggering of ovulation in human menopausal gonadotrophin-stimulated cycles: comparison between intravenously administered gonadotrophin-releasing hormone (100 and 500 micrograms), GnRH agonist (buserelin, 500 micrograms) and human chorionic gonadotrophin (10,000 IU). Hum Reprod . 1995; 10 56-62
145 Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes J M. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril . 1991; 56 213-220
146 Shalev E, Geslevich Y, Ben Ami M. Induction of pre-ovulatory luteinizing hormone surge by gonadotrophin-releasing hormone agonist for women at risk for developing the ovarian hyperstimulation syndrome. Hum Reprod . 1994; 9 417-419
147 Aboulghar M A, Mansour R T, Serour G I, Amin Y, Abbas A M, Salah I M. Ovarian superstimulation and intrauterine insemination for the treatment of unexplained infertility. Fertil Steril . 1993; 60 303-306
148 Chaffkin L M, Nulsen J C, Luciano A A, Metzger D A. A comparative analysis of the cycle fecundity rates associated with combined human menopausal gonadotropin (hMG) and intrauterine insemination (IUI) versus either hMG or IUI alone. Fertil Steril . 1991; 55 252-257
149 Cohlen B J, Vandekerckhove P, te Velde R E, Habbema J D. Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men (Cochrane Review). In: The Cochrane Library, Issue 1. Oxford: Update Software; 2002
150 DiMarzo S J, Kennedy J F, Young P E, Hebert S A, Rosenberg D C, Villanueva B. Effect of controlled ovarian hyperstimulation on pregnancy rates after intrauterine insemination. Am J Obstet Gynecol . 1992; 166 1607-1612
151 Nulsen J C, Walsh S, Dumez S, Metzger D A. A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility. Obstet Gynecol . 1993; 82 780-786
152 Peterson C M, Hatasaka H H, Jones K P, Poulson Jr M A, Carrell D T, Urry R L. Ovulation induction with gonadotropins and intrauterine insemination compared with in vitro fertilization and no therapy: a prospective, nonrandomized, cohort study and meta-analysis. Fertil Steril . 1994; 62 535-544
153 Dodson W C, Haney A F. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril . 1991; 55 457-467
154 Sengoku K, Tamate K, Takaoka Y, Morishita N, Ishikawa M. A randomized prospective study of gonadotrophin with or without gonadotrophin-releasing hormone agonist for treatment of unexplained infertility. Hum Reprod . 1994; 9 1043-1047
155 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
156 Olivennes F, Alvarez S, Bouchard P, Fanchin R, Salat-Baroux J, Frydman R. Thet use of a GnRH antagonist (cetrorelix) in a single dose protocol in IVF-embryo transfer: a dose finding study of 3 versus 2 mg. Hum Reprod . 1998; 13 2411-2414
157 Diedrich K, Diedrich C, Santos E. Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist cetrorelix during ovarian stimulation. Hum Reprod . 1994; 9 788-791
158 The Ganirelix Dose-Finding Study Group. A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum Reprod . 1998; 13 3023-3031
159 Obruca A, Fischl F, Huber J. Programming oocyte retrieval using oral contraceptive pretreatment before ovarian stimulation with a GnRH antagonist (Cetrotide) protocol. Hum Reprod . 2001; 16(Abstract book 1) 89
160 Naether O GJ, Sterzik K, Strehler E. Cetrotide and Gonal-F in IVF/ICSI patients receiving oral contraceptives for cycle programming prior to IVF/ICSI. Gynecol Endocrinol . 2001; 12 (12)
161 Van Loenen C D A, Huirne J AF, Schats R, Donnez J, Lambalk C B. An open label multicentre randomised parallel controlled phase II study to assess the feasibility of a new programming regimen using an oral contraceptive prior to the administration of recombinant FSH and an GnRH-antagonist in patients undergoing an ART (IVF/ICSI)-treatment. Hum Reprod . 2001; 16(Abstract book 1) 144
162 de Jong D, Macklon N S, Fauser B C. A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the "follicle-stimulating hormone window" combined with the gonadotropin-releasing hormone antagonist cetrorelix. Fertil Steril . 2000; 73 1051-1054
163 Rongieres-Bertrand C, Olivennes F, Righini C. Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (cetrorelix): a pilot study with minimal stimulation. Hum Reprod . 1999; 14 683-688
164 Albano C, Smitz J, Camus M, Riethmuller-Winzen H, Van Steirteghem A, Devroey P. Comparison of different doses of gonadotropin-releasing hormone antagonist cetrorelix during controlled ovarian hyperstimulation. Fertil Steril . 1997; 67 917-922
165 Gordon K, Danforth D R, Williams R F, Hodgen G D. New trends in combined use of gonadotropin-releasing hormone antagonists with gonadotropins or pulsatile gonadotropin-releasing hormone in ovulation induction and assisted reproductive technologies. Curr Opin Obstet Gynecol . 1992; 4 690-696
166 Dubourdieu S, Le Nestour E, Spitz I M, Charbonnel B, Bouchard P. The combination of gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH normalizes luteinizing hormone secretion in polycystic ovarian disease but fails to induce follicular maturation. Hum Reprod . 1993; 8 2056-2060
167 de Jong D, Macklon N S, Mannaerts B M, Coelingh Bennink H J, Fauser B C. High dose gonadotrophin-releasing hormone antagonist (ganirelix) may prevent ovarian hyperstimulation syndrome caused by ovarian stimulation for in-vitro fertilization. Hum Reprod . 1998; 13 573-575
168 Albano C, Felberbaum R E, Smitz J. Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group. Hum Reprod . 2000; 15 526-531
169 Borm G, Mannaerts B. The European Orgulatran Study Group. Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. Hum Reprod . 2000; 15 1490-1498
170 The European and Middle East Orgulatran Study Group. Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation. Hum Reprod . 2001; 16 644-651
171 Fluker M, Grifo J, Leader A. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil Steril . 2001; 75 38-45
172 Craft I, Gorgy A, Hill J, Menon D, Podsiadly B. Will GnRH antagonists provide new hope for patients considered "difficult responders" to GnRH agonist protocols?. Hum Reprod . 1999; 14 2959-2962
173 Nikolettos N, al Hasani S, Felberbaum R. Gonadotropin-releasing hormone antagonist protocol: a novel method of ovarian stimulation in poor responders. Eur J Obstet Gynecol Reprod Biol . 2001; 97 202-207
174 Akman M A, Erden H F, Tosun S B, Bayazit N, Aksoy E, Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod . 2001; 16 868-870
175 Akman M A, Erden H F, Tosun S B, Bayazit N, Aksoy E, Bahceci M. Addition of GnRH antagonist in cycles of poor responders undergoing IVF. Hum Reprod . 2000; 15 2145-2147
176 Ragni G, Vegetti W, Baroni E. Comparison of luteal phase profile in gonadotrophin stimulated cycles with or without a gonadotrophin-releasing hormone antagonist. Hum Reprod . 2001; 16 2258-2262
177 Olivennes F, Belaisch-Allart J, Emperaire J C. Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). Fertil Steril . 2000; 73 314-320
178 Al-Inany H, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception (Cochrane Review). In: The Cochrane Library, Issue 1 Oxford: Update Software; 2002
179 Ashton W T, Sisco R M, Kieczykowski G R. Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity. Bioorg Med Chem Lett . 1999; 9 2597-2602