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Meta-Analysis
. 2010 Dec 8;2010(12):CD008475.
doi: 10.1002/14651858.CD008475.pub2.

Gonadotrophin-releasing hormone analogues for pain associated with endometriosis

Julie Brown  1 , Alice Pan, Roger J Hart
Affiliations
Meta-Analysis

Gonadotrophin-releasing hormone analogues for pain associated with endometriosis

Julie Brown et al. Cochrane Database Syst Rev. .

Abstract

Editorial note: See https://pubmed.ncbi.nlm.nih.gov/37341141/ for a more recent review that covers this topic and has superseded this review.

Background: Endometriosis is a common gynaecological condition, characterised by the presence of endometrial tissue in sites other than the uterine cavity (excluding adenomyosis) that frequently presents with pain. The gonadotrophin-releasing hormone analogues (GnRHas) comprise one intervention that has been offered for pain relief in pre-menopausal women. GnRHas can be administered intranasally, by subcutaneous, or intramuscular injection. They are thought to result in down regulation of the pituitary and induce a hypogonadotrophic hypogonadal state.

Objectives: To determine the effectiveness and safety of GnRHas in the treatment of the painful symptoms associated with endometriosis.

Search strategy: Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group specialist register, CENTRAL, MEDLINE, EMBASE, PSYCInfo and CINAHL were conducted in April 2010 to identify relevant randomised controlled trials (RCTs).

Selection criteria: RCTs of GnRHas as treatment for pain associated with endometriosis versus no treatment, placebo, danazol, intra-uterine progestagens, or other GnRHas were included. Trials using add-back therapy, oral contraceptives, surgical intervention, GnRH antagonists or complementary therapies were excluded.

Data collection and analysis: Quality assessment and data extraction were performed independently by two reviewers. The primary outcome was pain relief. Relative risk was used as the measure of effect for dichotomous data. For continuous data, mean differences or standardised mean differences were used.

Main results: Forty one trials (n=4935 women) were included. The evidence suggested that GnRHas were more effective at symptom relief than no treatment/placebo. There was no statistically significant difference between GnRHas and danazol for dysmenorrhoea RR 0.98 (95%CI 0.92 to 1.04; P = 0.53). This equates to 3 fewer women per 1000 (95%CI 12 to 6) with symptomatic pain relief in the GnRHa group. More adverse events were reported in the GnRHa group. There was a benefit in overall resolution for GnRHas RR1.10 (95%CI 1.01 to 1.21, P=0.03) compared with danazol. There was no statistically significant difference in overall pain between GnRHas and levonorgestrel SMD -0.25 (95%CI -0.60 to 0.10, P=0.46). Evidence was limited on optimal dosage or duration of treatment for GnRHas. No route of administration appeared superior to another.

Authors' conclusions: GnRHas appear to be more effective at relieving pain associated with endometriosis than no treatment/placebo. There was no evidence of a difference in pain relief between GnRHas and danazol although more adverse events reported in the GnRHa groups. There was no evidence of a difference in pain relief between GnRHas and levonorgestrel and no studies compared GnRHas with analgesics.

PubMed Disclaimer

Conflict of interest statement

None

Figures

1
1
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.1 Relief of painful symptoms.
4
4
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.3 Relief of painful symptoms.
5
5
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.2 Overall resolution.
6
6
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.6 Side effects.
7
7
Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.3 relief of painful symptoms.
8
8
Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.2 rAFS score (400mcg vs 800mcg).
9
9
Forest plot of comparison: 7 GnRHa versus GnRHa (Length of Treatment), outcome: 7.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up.
1.1
1.1. Analysis
Comparison 1: GnRHas versus no treatment, Outcome 1: Relief of painful symptoms
2.1
2.1. Analysis
Comparison 2: GnRHas versus placebo, Outcome 1: Relief of painful symptoms
2.2
2.2. Analysis
Comparison 2: GnRHas versus placebo, Outcome 2: Side effects
2.3
2.3. Analysis
Comparison 2: GnRHas versus placebo, Outcome 3: Pain score
3.1
3.1. Analysis
Comparison 3: GnRHas versus danazol, Outcome 1: Relief of painful symptoms
3.2
3.2. Analysis
Comparison 3: GnRHas versus danazol, Outcome 2: Overall resolution
3.3
3.3. Analysis
Comparison 3: GnRHas versus danazol, Outcome 3: Relief of painful symptoms
3.4
3.4. Analysis
Comparison 3: GnRHas versus danazol, Outcome 4: rAFS
3.5
3.5. Analysis
Comparison 3: GnRHas versus danazol, Outcome 5: Improved rAFS score
3.6
3.6. Analysis
Comparison 3: GnRHas versus danazol, Outcome 6: Side effects
4.1
4.1. Analysis
Comparison 4: GnRHas versus intra‐ uterine progestagen device, Outcome 1: Relief of painful symptoms
4.2
4.2. Analysis
Comparison 4: GnRHas versus intra‐ uterine progestagen device, Outcome 2: rAFS/ASRM score
5.1
5.1. Analysis
Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 1: Side effects
5.2
5.2. Analysis
Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 2: rAFS score (400mcg vs 800mcg)
5.3
5.3. Analysis
Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 3: relief of painful symptoms
6.1
6.1. Analysis
Comparison 6: GnRHa versus GnRHa (Length of Treatment), Outcome 1: Relief of Painful Symptoms (3months vs 6months) at 6 months follow up
7.1
7.1. Analysis
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 1: Side effects (IN vs SC)
7.2
7.2. Analysis
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 2: rAFS score (IN vs SC)
7.3
7.3. Analysis
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 3: Relief of painful symptoms (IN versus IMdepot)
7.4
7.4. Analysis
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 4: Side effects (IN versus IMdepot)
7.5
7.5. Analysis
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 5: Improvement in symptoms (IN versus IMdepot)
7.6
7.6. Analysis
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 6: Relief of painful symptoms (IN versus SC)
See this image and copyright information in PMC

Comment in

Dataset described in

References

References to studies included in this review

Acien 1989 {published data only}
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Adamson 1994 {published data only}
    1. Adamson GD, Kwei L, Edgren RA. Pain of endometriosis: effects of nafarelin and danazol therapy. International Journal of Fertility & Menopausal Studies 1994;39(4):215-7. - PubMed
Agarwal 1997 {published data only}
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AN Zoladex 1996 {published data only}
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Burry 1989 {published data only}
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Crosignani 1996 {published data only}
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Dawood 1990 {published data only}
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Dlugi 1990 {published data only}
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Dmowski 1989a {published data only}
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Donnez 1989 {published data only}
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el‐Roeiy 1988 {published data only}
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Fedele 1989 {published data only}
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Fedele 1993 {published data only}
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Ferreira 2010 {published data only}
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Franssen 1992 {published data only}
    1. Franssen AM, Heijden PF, Thomas CM, Doesburg WH, Willemsen WN, Rolland R. On the origin and significance of serum CA-125 concentrations in 97 patients with endometriosis before, during, and after buserelin acetate, nafarelin, or danazol. Fertility & Sterility 1992;57(5):974-9. - PubMed
Fraser 1991 {published data only}
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Gomes 2007 {published data only}
    1. Gomes MK, Ferriani RA, Rosa e Silva JC, Japur de Sa Rosa e Silva AC, Vieira CS, Candido dos Reis FJ. The levonorgestrel-releasing intrauterine system and endometriosis staging.[see comment]. Fertility & Sterility 2007;87(5):1231-4. - PubMed
Henzl 1988 {published data only}
    1. Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. New England Journal of Medicine 1988;318(8):485-9. - PubMed
    1. Henzl MR. Role of nafarelin in the management of endometriosis. Journal of Reproductive Medicine 1989;34(12 Suppl):1021-4. - PubMed
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Henzl 1990a {published data only}
    1. Henzl MR, Monroe SE. Nafarelin: a new medical therapy for endometriosis. Progress in Clinical & Biological Research 1990;323:343-55. - PubMed
Hornstein 1995 {published data only}
    1. Hornstein M, Yuzpe A, Burry K, Heinrichs L, Orwoll E. A prospective randomised double-blind trial of 3 versus 6 months nafarelin therapy for symptoms of endometriosis. Fertility and Sterility 1992;58:S84. - PubMed
    1. Hornstein MD, Yuzpe AA, Burry KA, Heinrichs LR, Buttram VL Jr, et al. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertility & Sterility 1995;63(5):955-62. - PubMed
Jelley 1986 {published data only}
    1. Jelley RY, Magill PJ. The effect of LHRH agonist therapy in the treatment of endometriosis (English experience). Progress in Clinical & Biological Research 1986;225:227-38. - PubMed
    1. Jelley RY. Multicentre Open Comparative Study of Buserelin and Danazol in the Treatment of Endometriosis. British Journal of Clinical Practice 1986;48(Suppl):64-8.
Lemay 1988 {published data only}
    1. 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. American Journal of Obstetrics & Gynecology 1988;158(2):233-6. - PubMed
    1. Lemay A, Maheux R, Quesnel G, Bureau M, Faure N, Merat P. LH-RH agonist treatment of endometriosis. Contributions to Gynecology and Obstetrics 1987;16:247-53. - PubMed
Maouris 1991 {published data only}
    1. Maouris P, Dowsett M, Rose G, D E. Comparison of the endocrine effects of danazol and the LHRH agonist goserelin (Zoladex) in the treament of endometriosis. Silver Jubilee British Congress of Obstetrics and Gynaecology 1989:61.
    1. Maouris P. Pseudomenopause Treatment for Endometriosis: The Endocrine Effects of Danazol Compared with the use of the LH-RH Agonist Goserelin. Journal of Obstetrics & Gynaecology 1991;11:123-7.
Matalliotakis 2000 {published data only}
    1. Matalliotakis IM, Neonaki MA, Koumantaki YG, Goumenou AG, Kyriakou DS, Koumantakis EE. A randomized comparison of danazol and leuprolide acetate suppression of serum-soluble CD23 levels in endometriosis. Obstetrics & Gynecology 2000;95(6 Pt 1):810-3. - PubMed
Matta 1988 {published data only}
    1. Matta W, Shaw R. A comparative study between buserelin and danazol in the treatment of endometriosis. The British Journal of Clinical Practice 1988;40(4):69-72.
Miller 1990 {published data only}
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Miller 2000 {published data only}
    1. Miller JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin-releasing hormone agonist therapy: a double-blind, randomized, placebo-controlled trial. American Journal of Obstetrics & Gynecology 2000;182(6):1483-8. - PubMed
Minaguchi 1986 {published data only}
    1. Minaguchi H, Uemura T, Shirasu K. Clinical study on finding optimal dose of a potent LHRH agonist (buserelin) for the treatment of endometriosis--multicenter trial in Japan. Progress in Clinical & Biological Research 1986;225:211-25. - PubMed
NEET 1992 {published data only}
    1. Kennedy SH, Williams IA, Brodribb J, Barlow DH, Shaw RW. A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertility & Sterility 1990;53(6):998-1003. - PubMed
    1. NEET. Nafarelin for endometriosis: a large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up The Nafarelin European Endometriosis Trial Group (NEET) [see comments]. Fertility & Sterility 1992;57(3):514-22. - PubMed
Odukoya 1995 {published data only}
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Palagiano 1994 {published data only}
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Petta 2005 {published data only}
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    1. Vieira CS, Ferreira RA, Rosa e Silva JC, Rosa e Silva ACJS, Gomes MK, Ferriani RA. Comparative study of the influence of the levonorgestrel intra-uterine system and the GnRH analogues on cardiovascular risk markers in patients with endometriosis. Fertility & Sterility 2007;88(Suppl 1):211.
    1. Sa Rosa e Silva AC, Rosa e Silva JC, Nogueira AA, Petta CA, Abrao MS, Ferriani RA. The levonorgestrel-releasing intrauterine device reduces CA-125 serum levels in patients with endometriosis. Fertility & Sterility 2006;86(3):742-4. - PubMed
Rock 1993 {published data only}
    1. Allen TW. Zoladex versus danazol in endometriosis therapy. Journal of the American Osteopathic Association 1993;93(10):1013.
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Rolland 1990 {published data only}
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Rotondi 2002 {published data only}
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Shaw 1986 {published data only}
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Shaw 1990 {published data only}
    1. Shaw RW. Nafarelin in the treatment of pelvic pain caused by endometriosis. American Journal of Obstetrics & Gynecology 1990;162(2):574-6. - PubMed
Shaw 1992 {published data only}
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    1. Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Team. Fertility & Sterility 1992;58(2):265-72. - PubMed
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Skrzypulec 2004 {published data only}
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Tummon 1989 {published data only}
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Valimaki 1989 {published data only}
    1. Valimaki M, Nilsson CG, Roine R, Ylikorkala O. Comparison between the effects of nafarelin and danazol on serum lipids and lipoproteins in patients with endometriosis. The Journal of clinical endocrinology and metabolism 1989;69(6):1097-103. - PubMed
Wheeler 1992 {published data only}
    1. Wheeler JM, Knittle JD, Miller JD. Depot leuprolide acetate versus danazol in the treatment of women with symptomatic endometriosis: a multicenter, double-blind randomized clinical trial. II. Assessment of safety. The Lupron Endometriosis Study Group. American Journal of Obstetrics & Gynecology 1993;169(1):26-33. - PubMed
    1. Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results. American Journal of Obstetrics & Gynecology 1992;167(5):1367-71. - PubMed
Wright 1995 {published data only}
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References to studies excluded from this review

Adiyono 2006 {published data only}
    1. Adiyono W, Adisusianto I. The impact of combination laparoscopic surgery and GNRH analog on quality of life endometriosis patients. In: XVIII FIGO World Congress of Gynecology and Obstetrics. Vol. 2. 5-10 November Kuala Lumpur, Malaysia, 2006:143.
Cooke 1989 {published data only}
    1. Cooke ID, Thomas EJ. The medical treatment of mild endometriosis. Acta Obstetricia et Gynecologica Scandinavica - Supplement 1989;150:27-30. - PubMed
Dmowski 1989 {published data only}
    1. Dmowski WP. Comparitive Study of Buserelin Versus Danazol in the Management of Endometriosis. Gynecological Endocrinology 1989;3(Suppl 2):21-31.
Donnez 2004 {published data only}
    1. Donnez J, Dewart PJ, Hedon B, Perino A, Schindler AE, Blumberg J, et al. Equivalence of the 3-month and 28-day formulations of triptorelin with regard to achievement and maintenance of medical castration in women with endometriosis. Fertility & Sterility 2004;81(2):297-304. - PubMed
Franke 2000 {published data only}
    1. Franke H, Enschede K, Weijer P, Pennings T, Mooren M. Gonadotrophin-releasing hormone agonist plus 'add-back' for the treatment of endometriosis A prospective, randomized, placebo controlled, double blind trial. XVI FIGO World Congress of O & G. 2000;Abstract book 4:24. - PubMed
Fraser 1996 {published data only}
    1. Fraser IS, Healy DL, Torode H, Song JY, Mamers P, Wilde F. Depot goserelin and danazol pre-treatment before rollerball endometrial ablation for menorrhagia. Obstetrics & Gynecology 1996;87(4):544-50. - PubMed
Harada 2000 {published data only}
    1. Harada T. Empirical leuprolide treatment of women with suspected endometriosis was effective in reducing chronic pain. Evidence-based Obstetrics and Gynecology 2000;2:45.
Kiilholma 1995 {published data only}
    1. Kiilholma P, Tuimala R, Kivinen S, Korhonen M, Hagman E. Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis. Fertility and sterility 1995;64(5):903-8. - PubMed
Ling 1999 {published data only}
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Luciano 2004 {published data only}
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Magini 1993 {published data only}
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Matalliotakis 2004 {published data only}
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Newton 1996 {published data only}
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Roux 1995 {published data only}
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Sorensen 1997 {published data only}
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Surrey 1993 {published data only}
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Toomey 2003 {published data only}
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Vercellini 1994 {published data only}
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Vercellini 2009 {published data only}
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Warnock 1998 {published data only}
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References to studies awaiting assessment

Chan 1993 {published data only}
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Chen 2009 {published data only}
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References to other published versions of this review

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