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. 2023 Jun 21;6(6):CD014788.
doi: 10.1002/14651858.CD014788.pub2.

Gonadotropin-releasing hormone analogues for endometriosis

Veerle B Veth  1 , Majorie Ma van de Kar  2 , James Mn Duffy  3 , Madelon van Wely  4 , Velja Mijatovic  5 , Jacques Wm Maas  6
Affiliations

Gonadotropin-releasing hormone analogues for endometriosis

Veerle B Veth et al. Cochrane Database Syst Rev. .

Abstract

Background: Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decreased bone mineral density. In addition to assessing the effect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis who use GnRHas versus other treatment options.

Objectives: To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis.

Search methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial registries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies.

Selection criteria: We included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics, danazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents were also included in this review. DATA COLLECTION AND ANALYSIS: We used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in the most troublesome symptoms and patient satisfaction. Due to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk of selection bias. Sensitivity analysis including all studies was then performed.

Main results: Seventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies were serious risk of bias due to poor reporting of study methods, and serious imprecision. Trials comparing GnRHas versus no treatment We did not identify any studies. Trials comparing GnRHas versus placebo There may be a decrease in overall pain, reported as pelvic pain scores (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87, low-certainty evidence), dysmenorrhoea scores (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 85, low-certainty evidence), dyspareunia scores (RR 2.21; 95% CI 1.39 to 3.54, 1 RCT, n = 59, low-certainty evidence), and pelvic tenderness scores (RR 2.28; 95% CI 1.48 to 3.50, 1 RCT, n = 85, low-certainty evidence) after three months of treatment. We are uncertain of the effect for pelvic induration, based on the results found after three months of treatment (RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81, low-certainty evidence). Besides, treatment with GnRHas may be associated with a greater incidence of hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to 5.01, 1 RCT, n = 100, low-certainty evidence). Trials comparing GnRHas versus danazol For overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. We are uncertain about the effect on relief of overall pain, when a subdivision was made for overall pain (MD -0.30; 95% CI -1.66 to 1.06, 1 RCT, n = 41, very low-certainty evidence), pelvic pain (MD 0.20; 95% CI -0.26 to 0.66, 1 RCT, n = 41, very low-certainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20; 95% CI -0.77 to 0.37, 1 RCT, n = 41, very low-certainty evidence), pelvic induration (MD -0.10; 95% CI -0.59 to 0.39, 1 RCT, n = 41, very low-certainty evidence), and pelvic tenderness (MD -0.20; 95% CI -0.78 to 0.38, 1 RCT, n = 41, very low-certainty evidence) after three months of treatment. For pelvic pain (MD 0.50; 95% CI 0.10 to 0.90, 1 RCT, n = 41, very low-certainty evidence) and pelvic induration (MD 0.70; 95% CI 0.21 to 1.19, 1 RCT, n = 41, very low-certainty evidence), the complaints may decrease slightly after treatment with GnRHas, compared to danazol, for six months of treatment. Trials comparing GnRHas versus analgesics We did not identify any studies. Trials comparing GnRHas versus intra-uterine progestogens We did not identify any low risk of bias studies. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents There may be a slight decrease in bone mineral density (BMD) after 12 months treatment with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents for anterior-posterior spine (MD -7.00; 95% CI -7.53 to -6.47, 1 RCT, n = 41, very low-certainty evidence) and lateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence). AUTHORS' CONCLUSIONS: For relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD, there may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in favour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. Due to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement instruments, the results should be interpreted with caution.

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Conflict of interest statement

VV: none known

MvK: none known

JD: none known

JM: none known

MvW: co‐ed of Cochrane Gynaecology and Fertility Satellite

VM: none known

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: GnRHas versus placebo, Outcome 1: Relief of overall pain ‐ dichotomous ‐ decrease of pain
1.2
1.2. Analysis
Comparison 1: GnRHas versus placebo, Outcome 2: Adverse effects ‐ dichotomous
2.1
2.1. Analysis
Comparison 2: GnRHas versus placebo ‐ all studies included, Outcome 1: Relief of overall pain ‐ dichotomous
2.2
2.2. Analysis
Comparison 2: GnRHas versus placebo ‐ all studies included, Outcome 2: Relief of overall pain ‐ dichotomous ‐ decrease of pain
2.3
2.3. Analysis
Comparison 2: GnRHas versus placebo ‐ all studies included, Outcome 3: Relief of overall pain ‐ continuous
2.4
2.4. Analysis
Comparison 2: GnRHas versus placebo ‐ all studies included, Outcome 4: Adverse effects ‐ dichotomous
2.5
2.5. Analysis
Comparison 2: GnRHas versus placebo ‐ all studies included, Outcome 5: Quality of life ‐ continuous
3.1
3.1. Analysis
Comparison 3: GnRHas versus danazol, Outcome 1: Relief of overall pain ‐ dichotomous
3.2
3.2. Analysis
Comparison 3: GnRHas versus danazol, Outcome 2: Relief of overall pain ‐ continuous
3.3
3.3. Analysis
Comparison 3: GnRHas versus danazol, Outcome 3: Adverse effects ‐ dichotomous
4.1
4.1. Analysis
Comparison 4: GnRHas versus danazol ‐ all studies included, Outcome 1: Relief of overall pain ‐ dichotomous
4.2
4.2. Analysis
Comparison 4: GnRHas versus danazol ‐ all studies included, Outcome 2: Relief of overall pain ‐ continuous
4.3
4.3. Analysis
Comparison 4: GnRHas versus danazol ‐ all studies included, Outcome 3: Bone mineral density of spinal bone mass ‐ continuous
4.4
4.4. Analysis
Comparison 4: GnRHas versus danazol ‐ all studies included, Outcome 4: Adverse effects ‐ dichotomous
4.5
4.5. Analysis
Comparison 4: GnRHas versus danazol ‐ all studies included, Outcome 5: Improvement of most troublesome symptoms ‐ dichotomous
5.1
5.1. Analysis
Comparison 5: GnRHas versus intra‐uterine progestagen device ‐ all studies included, Outcome 1: Relief of overall pain ‐ continuous
5.2
5.2. Analysis
Comparison 5: GnRHas versus intra‐uterine progestagen device ‐ all studies included, Outcome 2: Quality of life ‐ continuous
6.1
6.1. Analysis
Comparison 6: GnRHas versus oral or injectable progestogens, Outcome 1: Relief of overall pain ‐ continuous
6.2
6.2. Analysis
Comparison 6: GnRHas versus oral or injectable progestogens, Outcome 2: Adverse effects ‐ dichotomous
7.1
7.1. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 1: Relief of overall pain ‐ dichotomous
7.2
7.2. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 2: Relief of overall pain ‐ continuous
7.3
7.3. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 3: Bone mineral density of spinal bone mass ‐ continuous
7.4
7.4. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 4: Adverse effects ‐ dichotomous
7.5
7.5. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 5: Adverse effects ‐ continuous
7.6
7.6. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 6: Quality of life ‐ continuous
7.7
7.7. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 7: Improvement of most troublesome symptoms ‐ dichotomous
7.8
7.8. Analysis
Comparison 7: GnRHas versus oral or injectable progestogens ‐ all studies included, Outcome 8: Improvement of most troublesome symptoms ‐ continuous
8.1
8.1. Analysis
Comparison 8: GnRHas versus gestrinone ‐ all studies included, Outcome 1: Relief of overall pain ‐ continuous
8.2
8.2. Analysis
Comparison 8: GnRHas versus gestrinone ‐ all studies included, Outcome 2: Bone mineral density of spinal bone mass ‐ continuous
8.3
8.3. Analysis
Comparison 8: GnRHas versus gestrinone ‐ all studies included, Outcome 3: Adverse effects ‐ dichotomous
9.1
9.1. Analysis
Comparison 9: GnRHas versus GnRHas (varying dosage) ‐ all studies included, Outcome 1: Relief of overall pain ‐ 200 μg versus 400 μg nafarelin ‐ continuous
9.2
9.2. Analysis
Comparison 9: GnRHas versus GnRHas (varying dosage) ‐ all studies included, Outcome 2: Relief of overall pain ‐ 400 μg versus 800 μg nafarelin ‐ dichotomous
9.3
9.3. Analysis
Comparison 9: GnRHas versus GnRHas (varying dosage) ‐ all studies included, Outcome 3: Adverse effects ‐ 200 μg versus 400 μg nafarelin ‐ dichotomous
9.4
9.4. Analysis
Comparison 9: GnRHas versus GnRHas (varying dosage) ‐ all studies included, Outcome 4: Adverse effects ‐ 3.75 mg versus 1.88 mg leuprolide acetate ‐ continuous
9.5
9.5. Analysis
Comparison 9: GnRHas versus GnRHas (varying dosage) ‐ all studies included, Outcome 5: Improvement of most troublesome symptoms ‐ 400 μg versus 800 μg nafarelin ‐ dichotomous
10.1
10.1. Analysis
Comparison 10: GnRHas versus GnRHas (duration of treatment) ‐ all studies included, Outcome 1: Relief of overall pain ‐ 3 months vs 6 months ‐ continuous
10.2
10.2. Analysis
Comparison 10: GnRHas versus GnRHas (duration of treatment) ‐ all studies included, Outcome 2: Bone mineral density of spinal bone mass ‐ 3 months vs 6 months ‐ continuous
10.3
10.3. Analysis
Comparison 10: GnRHas versus GnRHas (duration of treatment) ‐ all studies included, Outcome 3: Bone mineral density of proximal femoral bone ‐ 3 months vs 6 months ‐ continuous
11.1
11.1. Analysis
Comparison 11: GnRHas versus GnRHas (route of administration), Outcome 1: Relief of overall pain ‐ IN versus SC ‐ dichotomous
11.2
11.2. Analysis
Comparison 11: GnRHas versus GnRHas (route of administration), Outcome 2: Adverse effects ‐ IN vs SC ‐ dichotomous
12.1
12.1. Analysis
Comparison 12: GnRHas versus GnRHas (route of administration) ‐ all studies included, Outcome 1: Relief of overall pain ‐ IN versus SC ‐ dichotomous
12.2
12.2. Analysis
Comparison 12: GnRHas versus GnRHas (route of administration) ‐ all studies included, Outcome 2: Relief of overall pain ‐ IN versus IM ‐ dichotomous
12.3
12.3. Analysis
Comparison 12: GnRHas versus GnRHas (route of administration) ‐ all studies included, Outcome 3: Adverse effects ‐ IN vs SC ‐ dichotomous
12.4
12.4. Analysis
Comparison 12: GnRHas versus GnRHas (route of administration) ‐ all studies included, Outcome 4: Adverse effects ‐ IN versus IM depot ‐ dichotomous
12.5
12.5. Analysis
Comparison 12: GnRHas versus GnRHas (route of administration) ‐ all studies included, Outcome 5: Bone mineral density of spinal bone mass ‐ IN vs IM depot ‐ continuous
13.1
13.1. Analysis
Comparison 13: GnRHas versus GnRHas (different treatment regimens) ‐ all studies included, Outcome 1: Relief of overall pain ‐ monthly versus 3‐monthly depot leuprolide acetate ‐ continuous
13.2
13.2. Analysis
Comparison 13: GnRHas versus GnRHas (different treatment regimens) ‐ all studies included, Outcome 2: Adverse effects ‐ monthly versus 3‐monthly depot leuprolide acetate ‐ dichotomous
14.1
14.1. Analysis
Comparison 14: GnRHas versus GnRHas in conjunction with add‐back therapy ‐ all studies included, Outcome 1: Relief of overall pain ‐ dichotomous
14.2
14.2. Analysis
Comparison 14: GnRHas versus GnRHas in conjunction with add‐back therapy ‐ all studies included, Outcome 2: Relief of overall pain ‐ continuous
14.3
14.3. Analysis
Comparison 14: GnRHas versus GnRHas in conjunction with add‐back therapy ‐ all studies included, Outcome 3: Bone mineral density of spinal bone mass ‐ continuous
14.4
14.4. Analysis
Comparison 14: GnRHas versus GnRHas in conjunction with add‐back therapy ‐ all studies included, Outcome 4: Adverse effects ‐ dichotomous
14.5
14.5. Analysis
Comparison 14: GnRHas versus GnRHas in conjunction with add‐back therapy ‐ all studies included, Outcome 5: Quality of life ‐ continuous
14.6
14.6. Analysis
Comparison 14: GnRHas versus GnRHas in conjunction with add‐back therapy ‐ all studies included, Outcome 6: Improvement of most troublesome symptoms ‐ continuous
15.1
15.1. Analysis
Comparison 15: GnRHas versus GnRHas in conjunction with calcium‐regulating agents, Outcome 1: Bone mineral density of spinal bone mass ‐ continuous
15.2
15.2. Analysis
Comparison 15: GnRHas versus GnRHas in conjunction with calcium‐regulating agents, Outcome 2: Improvement of most troublesome symptoms ‐ dichotomous
16.1
16.1. Analysis
Comparison 16: GnRHas versus GnRHas in conjunction with calcium‐regulating agents ‐ all studies included, Outcome 1: Bone mineral density of spinal bone mass ‐ continuous
16.2
16.2. Analysis
Comparison 16: GnRHas versus GnRHas in conjunction with calcium‐regulating agents ‐ all studies included, Outcome 2: Improvement of most troublesome symptoms ‐ dichotomous
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Dataset use reported in

References

References to studies included in this review

Abdou 2018 {published data only}
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Fraser 1991 {published data only}
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Freundl 1998 {published data only}
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Gnoth 1999 {published data only}
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Gomes 2007 {published data only}
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Harada 2009 {published data only}
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Henzl 1988 {published data only}
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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 & 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. [PMID: ] - PubMed
Hornstein 1998 {published data only}
    1. Hornstein MD, Surrey ES, Weisberg GW, Casino LA LUPRON add-back study group. Leuprolide acetate depot and hormonal add-back in endometriosis: A 12- month study. Obstetrics and Gynecology Jan 1998;1:16-24. [DOI: 10.1016/s0029-7844(97)00620-0] - DOI - PubMed
Howell 1995 {published data only}
    1. Howell R, Edmonds DK, Dowsett M, Crook D, Lees B, Stevenson JC. Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial. Fertility & Sterility 1995;64(3):474-481. [DOI: 10.1016/s0015-0282(16)57779-6.] - DOI - PubMed
Hurst 2000 {published data only}
    1. Hurst BS, Gardner SC, Tucker KE, Awoniyi CA, Schlaff WD. Delayed oral estradiol combined with leuprolide increases endometriosis-related pain. Journal of the Society of Laparoendoscopic Surgeons 2000;4:97-101. [PMID: ] - PMC - PubMed
Irahara 2001 {published data only}
    1. Irahara M, Uemura H, Yasui T, Kinoshita H, Yamada M, Tezuka M, et al. Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynecologic and Obstetric Investigation 2001;52:217-222. [DOI: 10.1159/000052978] - DOI - 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.
Kennedy 1990 {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 June 1990;53(6):998-1003. [DOI: 10.1016/s0015-0282(16)53574-2] - DOI - PubMed
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 & Sterility 1995;64(5):903-908. [DOI: 10.1016/s0015-0282(16)57900-x] - DOI - PubMed
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. [DOI: 10.1016/0002-9378(88)90128-7] - DOI - 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
Ling 1999 {published data only}
    1. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic pain study group. Obstetrics & Gynecology 1999;93(1):51-58. [DOI: 10.1016/s0029-7844(98)00341-x] - DOI - PubMed
Mäkäräinen 1996 {published data only}
    1. Makarainen L, Rönnberg L, Kauppila A. Medroxyprogesterone acetate supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in endometriosis. Fertility & Sterility 1996;65(1):29-34. [DOI: 10.1016/s0015-0282(16)58023-6] - DOI - PubMed
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):1483-1488. [DOI: 10.1067/mob.2000.106846] - DOI - 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. [PMID: ] - PubMed
Moghissi 1998 {published data only}
    1. Moghissi KS, Schlaff WD, Olive DL, Skinner MA, Yin H. Goserelin acetate (Zoladex) with or without hormone replacement. Therapy for the treatment of endometriosis. Fertility & Sterility June 1998;69(6):1056-1062. [DOI: 10.1016/s0015-0282(98)00086-7] - DOI - 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) . Fertility & Sterility 1992;57(3):514-22. [PMID: ] - PubMed
Odukoya 1995 {published data only}
    1. Odukoya OA, Bansal A, Wilson AP, Weetman AP, Cooke ID. Serum-soluble CD23 in patients with endometriosis and the effect of treatment with danazol and leuprolide acetate depot injection. Human Reproduction 1995;10(4):942-946. [DOI: 10.1093/oxfordjournals.humrep.a136067] - DOI - PubMed
Orwoll 1994 {published data only}
    1. Orwoll ES, Yuzpe AA, Burry KA, Heinrichs L, Buttram VC, Hornstein MD. Nafarelin therapy in endometriosis: long-term effects on bone mineral density. American Journal of Obstetrics and Gynecology Nov 1994;171(5):1221-1225. [DOI: 10.1016/0002-9378(94)90136-8] - DOI - PubMed
Ozaki 2020 {published data only}
    1. Ozaki R, Kumakiri J, Jinushi M, Ikuma S, Murakami K, Kawasaki Y, et al. Comparison of effect of preoperative dienogest and gonadotropin‑releasing hormone agonist administration on laparoscopic cystectomy for ovarian endometriomas. Archives of Gynecology and Obstetrics July 2020;302:969-976. [DOI: 10.1007/s00404-020-05691-3] - DOI - PubMed
Palagiano 1994 {published data only}
    1. Palagiano A, Capuano V. Medical treatment of endometriosis: comparative study of leuprolide acetate and danazol. Minerva Ginecologica 1994;46(4):173-7. [PMID: ] - PubMed
Petta 2005 {published data only}
    1. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa ESJC, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Human Reproduction 2005;20(7):1993-8. [DOI: 10.1093/humrep/deh869] - DOI - PubMed
    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.
    1. Rock JA, Truglia JA, Caplan RJ. Zoladex (goserelin acetate implant) in the treatment of endometriosis: a randomized comparison with danazol. Obstetrics & Gynecology 1993;82(2):198-205. [PMID: ] - PubMed
    1. Rock JA. A multicenter comparison of GnRH agonist (Zoladex) and danazol in the treatment of endometriosis . Fertility & Sterility 1991;56(pp.s49).
Rolland 1990 {published data only}
    1. Rolland R, Heijden PF. Nafarelin versus danazol in the treatment of endometriosis. American Journal of Obstetrics & Gynecology 1990;162(2):586-8. [DOI: 10.1016/0002-9378(90)90437-c] - DOI - PubMed
Rotondi 2002 {published data only}
    1. Rotondi M, Labriola D, Ammaturo FP, Amato G, Carella C, Izzo A, et al. Depot leuprorelin acetate versus danazol in the treatment of infertile women with symptomatic endometriosis. European Journal of Gynaecological Oncology 2002;23(6):523-526. [PMID: ] - PubMed
Roux 1995 {published data only}
    1. Roux C, Pelissier C, Listrat V, Kolta S, Simonetta C, Guignard M, et al. Bone loss during gonadotropin releasing hormone agonist treatment and use of nasal calcitonin. Osteoporosis International 1995;5:185-190. [DOI: 10.1007/BF02106098] - DOI - PubMed
Schlaff 2006 {published data only}
    1. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertility & Sterility February 2006;85(2):314-325. [DOI: 10.1016/j.fertnstert.2005.07.1315.] - DOI - PubMed
Shaw 1986 {published data only}
    1. Shaw RW, Matta W. Reversible pituitary ovarian suppression induced by an LHRH agonist in the treatment of endometriosis - comparison of two dose regimens. Clinical Reproduction and Fertility 1986;4(5):329-36. [PMID: ] - PubMed
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. [DOI: 10.1016/0002-9378(90)90433-8] - DOI - PubMed
Sillem 1999 {published data only}
    1. Sillem M, Parviz M, Woitge HW, Kiesel L, Ulrich U, Holst T, et al. Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin. Experimental and Clinical Endocrinology & Diabetes 1999;107:379-385. [DOI: 10.1055/s-0029-1212129] - DOI - PubMed
Skrzypulec 2004 {published data only}
    1. Skrzypulec V, Walaszek A, Drosdzol A, Nowosielski K, Piela B, Rozmus-Warcholinska W. Influence of GnRH analogue on the intensification of endometriosis symptoms and infertility treatment. Wiadomosci Lekarskie 2004;57 Suppl 1:301-4. [PMID: ] - PubMed
Strowitzki 2012 {published data only}
    1. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. International Journal of Gynecology and Obstetrics 2012;117(3):228-233. [DOI: 10.1016/j.ijgo.2012.01.009] - DOI - PubMed
    1. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Human Reproduction January 2010;25(3):633-641. [DOI: 10.1093/humrep/dep46] - DOI - PubMed
Surrey 1992 {published data only}
    1. Surrey ES, Judd HL. Reduction of vasomotor symptoms and bone mineral density loss with combined norethindrone and long-acting gonadotropin-releasing hormone agonist therapy of symptomatic endometriosis: A prospective randomized trial. Journal of Clinical Endocrinology and Metabolism 1992;75(2):558-563. [DOI: 10.1210/jcem.75.2.1386374] - DOI - PubMed
Surrey 2002 {published data only}
    1. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstetrics and Gynecology 2002;99(5 Pt 1):709-719. [DOI: 10.1016/s0029-7844(02)01945-2] - DOI - PubMed
Tahara 2000 {published data only}
    1. Tahara M, Matsuoka T, Yokoi T, Tasaka K, Kurachi H, Murata Y. Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy ("draw-back" therapy). Fertility & Sterility 2000;73(4):799-804. [DOI: 10.1016/s0015-0282(99)00636-6] - DOI - PubMed
Tang 2017 {published data only}
    1. Tang H, Wu R, Li X, Zhou Y, Liu Z, Wang C, Chen Y, et al. Curative effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist on stage III–IV endometriosis: Randomized controlled study. The Journal of Obstetrics and Gynaecology Research October 2017;43(10):1550-1554. [DOI: 10.1111/jog.13420] - DOI - PubMed
Tummon 1988 {published data only}
    1. Tummon IS, Ali A, Pepping ME, Radwanska E, Binor Z, Dmowski WP. Bone mineral density in women with endometriosis before and during ovarian suppression with gonadotropin-releasing hormone agonists or danazol. Fertility & Sterility May 1988;49(5):792-796. [PMID: ] - PubMed
Tummon 1989 {published data only}
    1. Tummon IS, Pepping ME, Binor Z, Radwanska E, Dmowski WP. A randomized, prospective comparison of endocrine changes induced with intranasal leuprolide or danazol for treatment of endometriosis. Fertility & Sterility 1989;51(3):390-4. [DOI: 10.1016/s0015-0282(16)60542-3] - DOI - PubMed
Vercellini 1994 {published data only}
    1. Vercellini P, Trespidi L, Panazza S, Bramante T, Mauro F, Crosignani PG. Very low dose danazol for relief of endometriosis-associated pelvic pain: a pilot study. Fertility & Sterility 1994;62(6):1136-42. [PMID: ] - PubMed
Vercellini 1996 {published data only}
    1. Vercellini P, Soma M, Moro GL. Gestrinone versus a gonadotropin-releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: A multicenter, randomized, double-blind study. Fertility & Sterility 196;66(6):911-919. [DOI: 10.1016/s0015-0282(16)58682-8] - DOI - 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. American Journal of Obstetrics & Gynecology 1992;167(5):1367-71. [DOI: 10.1016/0002-9378(93)90126-4.] - DOI - PubMed
Whitehouse 1990 {published data only}
    1. Whitehouse RW, Adams JE, Bancroft K, Vaughan-Williams CA, Elstein M. The effects of nafarelin and danazol on vertebral trabecular bone mass in patients with endometriosis. Clinical Endocrinology 1990;33(3):365-373. [DOI: 10.1016/s0015-0282(16)58682-8] - DOI - PubMed
Zupi 2005 {published data only}
    1. Zupi E, Sbracia M, Marconi D, Sorrenti G, Zullo F, Palomba S. Role of medical therapy in the treatment of endometriosis associated pelvic pain: a randomized controlled study. Journal of Minimally Invasive Gynecology 2005;12(5):S6. [DOI: 10.3390/jcm10051085] - DOI

References to studies excluded from this review

Acien 1989 {published data only}
    1. Acien P, Shaw RW, Irvine L, Burford GRG. CA 125 levels in endometriosis patients before, during and after treatment with danazol or LHRH agonists. European Journal of Gynaecological Oncology 1989;32(1):241-6. - PubMed
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.
Agarwal 2015 {published data only}
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Al‐Azemi 2009 {published data only}
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Bergqvist 1990 {published data only}
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Chan 1993 {published data only}
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Chen 2009 {published data only}
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Choktanasiri 2001 {published data only}
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Claesson 1989 {published data only}
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Cooke 1989 {published data only}
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Dawood 1990 {published data only}
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Dmowski 1989 {published data only}
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Dodin 1991 {published data only}
    1. Dodin S, Lemay A, Maheux R, Dumont M, Turcot-Lemay L. Bone mass in endometriosis patients treated with GnRH agonist implant or danazol. Obstetrics and Gynecology 1991;77(3):410-415. [PMID: ] - PubMed
Donnez 1989 {published data only}
    1. Donnez J, Nisolle-Pochet M, Clerckx-Braun F, Sandow J, Casanas-Roux F. Administration of nasal buserelin as compared with subcutaneous buserelin implant for endometriosis. Fertility & Sterility 1989;52(1):27-30. - PubMed
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
Eldred 1992 {published data only}
    1. Eldred JM, Haynes PJ, Thomas EJ. A randomized double blind placebo controlled trial of the effects on bone metabolism of the combination of nafarelin acetate and norethisterone. Clinical Endocrinology 1992;37:354-359. [DOI: 10.1111/j.1365-2265.1992.tb02338.x] - DOI - PubMed
el‐Roeiy 1988 {published data only}
    1. el-Roeiy A, Dmowski WP, Gleicher N, Radwanska E, Harlow L, Binor Z, et al. Danazol but not gonadotropin-releasing hormone agonists suppresses autoantibodies in endometriosis. Fertility & Sterility 1988;50(6):864-71. - PubMed
Fedele 1993 {published data only}
    1. Fedele L, Bianchi S, Bocciolone L, Di Nola G, Franchi D. Buserelin acetate in the treatment of pelvic pain associated with minimal and mild endometriosis: a controlled study. Fertility & Sterility 1993;59(3):516-21. - PubMed
Fernandez 2004 {published data only}
    1. Fernandez H, Lucas C, Hédon B , Meyer JL, Mayenga JM and Roux C. One year comparison between two add-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomized double-blind trial. Human Reproduction April 2004;19:1465-1471. [DOI: 10.1093/humrep/deh250] - DOI - PubMed
Ferrero 2011 {published data only}
    1. Ferrero S, Venturini PL, Gillott DJ, Remorgida V. Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of endometriosis related pain symptoms: a randomized controlled trial. Reproductive Biology and Endocrinology 2011;9:1-7. [DOI: 10.1186/1477-7827-9-88] - DOI - PMC - PubMed
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 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.
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
Imani 2009 {published data only}
    1. Imani R, Thai-Cuarto D, Jimenez R, Burke J, Kroll R, O'Brien C. Petal study: Safety, tolerability and effectiveness of elagolix, an oral GnRH antagonist for endometriosis. In: Fertility & Sterility. Vol. 92. 2009:S111-S112. [DOI: 10.1016/j.fertnstert.2009.07.1100] - DOI
Lindsay 1996 {published data only}
    1. Lindsay PC, Shaw RW, Bennink HJC, Kicovic P. The effect of add-back treatment with tibolone (Livial) on patients treated with the gonadotropin-releasing hormone agonist triptorelin (decapeptyl). Fertility & Sterility 1996;65(2):342-348. [DOI: 10.1016/s0015-0282(16)58096-0] - DOI - PubMed
Luciano 2004 {published data only}
    1. Luciano AA. Leuprolide acetate in the management of endometriosis-associated pain: A multicenter, evaluator-blind, comparative clinical trial. Global Congress of Gynecologic Endoscopy 33rd Annual Meeting of the AAGL "Advancing Minimally Invasive Gynecology Worldwide" 2004;11(Suppl 3):s5.
Magini 1993 {published data only}
    1. Magini A, Pellegrini S, Tavella K, Forti G, Massi GB, Serio M. Estrogenic suppression by different administration schedules of goserelin depot for treatment of endometriosis. Journal of Endocrinological Investigation 1993;16(10):775-80. - PubMed
Maouris 1991 {published data only}
    1. Maouris P, Dowsett M, Nichols J, Rose G, Edmonds DK. Pseudomenopause treatment for endometriosis: The endocrine effects of danazol compared with the use of the LH-RH agonist goserelin. Journal of Obstetrics & Gynaecology 1991;11:123-127. [DOI: 10.1016/s0015-0282(16)58023-6] - DOI
    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.
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):810-813. [DOI: 10.1016/s0029-7844(99)00635-3] - DOI - PubMed
Matalliotakis 2004 {published data only}
    1. Matalliotakis IM, Arici A, Goumenou AG, Katassos T, Karkavitsas N, Koumantakis EE. Comparison of the effects of leuprorelin acetate and danazol treatments on serum CA-125 levels in women with endometriosis. International Journal of Fertility & Womens Medicine 2004;49(2):75-8. - 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}
    1. Miller JD. Leuprolide acetate for the treatment of endometriosis. Progress in Clinical & Biological Research 1990;323:337-41. - PubMed
Mukherjee 1996 {published data only}
    1. Mukherjee T, Barad D, Turk R, Reeman R. A randomized, placebo-controlled study on the effect of cyclic intermittent etidronate therapy on the bone mineral density changes associated with six months of gonadotropin-releasing hormone agonist treatment. American Journal of Obstetrics and Gynecology 1997;175(1):105-109. [DOI: 10.1016/S0002-9378(96)70258-2] - DOI - PubMed
Newton 1996 {published data only}
    1. Newton C, Slota D, Yuzpe AA, Tummon IS. Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study. Fertility & Sterility 1996;65(6):1253-5. - PubMed
Pierce 2000 {published data only}
    1. Pierce SJ, Gazvani RM, Farquharson RG. 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. Fertility & Sterility Nov 2000;74(5):964-968. [DOI: 10.1016/s0015-0282(00)01537-5] - DOI - PubMed
Ripps 2003 {published data only}
    1. Ripps BA, VanGilder K, Minhas B, Welford M, Mamish Z. Alendronate for the prevention of bone mineral loss during gonadotropin-releasing hormone agonist therapy. The Journal of Reproductive Medicine October 2003 ;48(10):761-766. [PMID: ] - PubMed
Shaw 1992 {published data only}
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Shaw 2001 {published data only}
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References to studies awaiting assessment

Aisaka 2000 {published data only}
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References to other published versions of this review

Brown 2010
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Publication types