, Volume 78, Issue 10, pp 995–1012 | Cite as

Current and Emerging Therapeutics for the Management of Endometriosis

  • Simone Ferrero
  • Fabio Barra
  • Umberto Leone Roberti Maggiore
Review Article


Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives (COCs) and progestins, available for multiple routes of administration, are effective first-line hormonal options. In fact, several randomized controlled trials (RCTs) demonstrated that they succeed in improving pain symptoms in the majority of patients, are well tolerated and not expensive. Second-line therapy is represented by gonadotropin-releasing hormone (GnRH) agonists. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). The use of danazol is limited by the large availability of other better-tolerated hormonal drugs. Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be administered only in women with symptoms refractory to other conventional therapies in a clinical research setting. Promising preliminary data have emerged from multicenter Phase III trials on elagolix, a new oral GnRH antagonist but non-inferiority RCT data are required to compare elagolix with first-line therapies for endometriosis.


Compliance with Ethical Standards


This paper was not funded.

Conflict of interest

Simone Ferrero, Fabio Barra, Umberto Leone Roberti Maggiore declare that they have no conflict of interest.


  1. 1.
    Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75.PubMedCrossRefGoogle Scholar
  2. 2.
    Ferrero S, Arena E, Morando A, Remorgida V. Prevalence of newly diagnosed endometriosis in women attending the general practitioner. Int J Gynaecol Obstet. 2010;110(3):203–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Guerriero S, Condous G, Van den Bosch T, Valentin L, Leone FP, Van Schoubroeck D, et al. Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol. 2016;48(3):318–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Holsbeke C, Van Calster B, Guerriero S, Savelli L, Paladini D, Lissoni AA, et al. Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol. 2010;35(6):730–40.PubMedGoogle Scholar
  5. 5.
    Bazot M, Darai E. Diagnosis of deep endometriosis: clinical examination, ultrasonography, magnetic resonance imaging, and other techniques. Fertil Steril. 2017;108(6):886–94.PubMedCrossRefGoogle Scholar
  6. 6.
    Jacobson TZ, Duffy JM, Barlow D, Koninckx PR, Garry R. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2009;4:CD001300.Google Scholar
  7. 7.
    Shakiba K, Bena JF, McGill KM, Minger J, Falcone T. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111(6):1285–92.PubMedCrossRefGoogle Scholar
  8. 8.
    Fedele L, Bianchi S, Zanconato G, Berlanda N, Borruto F, Frontino G. Tailoring radicality in demolitive surgery for deeply infiltrating endometriosis. Am J Obstet Gynecol. 2005;193(1):114–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Barra F, Scala C, Ferrero S. Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis. Expert Opin Drug Metab Toxicol. 2018;14(4):399–415.PubMedCrossRefGoogle Scholar
  11. 11.
    Marjoribanks J, Ayeleke RO, Farquhar C, Proctor M. Nonsteroidal anti–inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev. 2015;7:CD001751.Google Scholar
  12. 12.
    Kauppila A, Ronnberg L. Naproxen sodium in dysmenorrhea secondary to endometriosis. Obstet Gynecol. 1985;65(3):379–83.PubMedGoogle Scholar
  13. 13.
    Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal anti–inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017;1:CD004753.PubMedGoogle Scholar
  14. 14.
    Ferrero S, Alessandri F, Racca A, Maggiore ULR. Treatment of pain associated with deep endometriosis: alternatives and evidence. Fertil Steril. 2015;104(4):771–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low–dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril. 2008;90(5):1583–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril. 1993;60(1):75–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Vercellini P, De Giorgi O, Mosconi P, Stellato G, Vicentini S, Crosignani PG. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertil Steril. 2002;77(1):52–61.PubMedCrossRefGoogle Scholar
  18. 18.
    Sesti F, Pietropolli A, Capozzolo T, Broccoli P, Pierangeli S, Bollea MR, et al. Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III–IV. A randomized comparative trial. Fertil Steril. 2007;88(6):1541–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Parazzini F, Di Cintio E, Chatenoud L, Moroni S, Ardovino I, Struzziero E, et al. Estroprogestin vs. gonadotrophin agonists plus estroprogestin in the treatment of endometriosis–related pelvic pain: a randomized trial. Gruppo Italiano per lo Studio dell’Endometriosi. Eur J Obstet Gynecol Reprod Biol. 2000;88(1):11–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Guzick DS, Huang LS, Broadman BA, Nealon M, Hornstein MD. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril. 2011;95(5):1568–73.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Cheewadhanaraks S, Choksuchat C, Dhanaworavibul K, Liabsuetrakul T. Postoperative depot medroxyprogesterone acetate versus continuous oral contraceptive pills in the treatment of endometriosis-associated pain: a randomized comparative trial. Gynecol Obstet Invest. 2012;74(2):151–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Scala C, Maggiore ULR, Barra F, Venturini PL, Ferrero S. Norethindrone acetate versus extended-cycle oral contraceptive (Seasonique((R))) in the treatment of endometriosis symptoms: A prospective open-label comparative study. Eur J Obstet Gynecol Reprod Biol. 2018;222:89–94.PubMedCrossRefGoogle Scholar
  23. 23.
    Vercellini P, Barbara G, Somigliana E, Bianchi S, Abbiati A, Fedele L. Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis. Fertil Steril. 2010;93(7):2150–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Maggiore ULR, Remorgida V, Scala C, Tafi E, Venturini PL, Ferrero S. Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: A prospective open-label comparative study. Acta Obstet Gynecol Scand. 2014;93(3):239–47.CrossRefGoogle Scholar
  25. 25.
    Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev. 2012;3:CD002122.Google Scholar
  26. 26.
    Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Crosignani PG. Treatment of symptomatic rectovaginal endometriosis with an estrogen-progestogen combination versus low-dose norethindrone acetate. Fertil Steril. 2005;84(5):1375–87.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferrero S, Camerini G, Ragni N, Venturini PL, Biscaldi E, Remorgida V. Norethisterone acetate in the treatment of colorectal endometriosis: a pilot study. Hum Reprod. 2010;25(1):94–100.PubMedCrossRefGoogle Scholar
  28. 28.
    Vercellini P, Somigliana E, Consonni D, Frattaruolo MP, De Giorgi O, Fedele L. Surgical versus medical treatment for endometriosis-associated severe deep dyspareunia: I. Effect on pain during intercourse and patient satisfaction. Hum Reprod. 2012;27(12):3450–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Vercellini P, Frattaruolo MP, Somigliana E, Jones GL, Consonni D, Alberico D, et al. Surgical versus low-dose progestin treatment for endometriosis-associated severe deep dyspareunia II: effect on sexual functioning, psychological status and health–related quality of life. Hum Reprod. 2013;28(5):1221–30.PubMedCrossRefGoogle Scholar
  30. 30.
    Morotti M, Venturini PL, Biscaldi E, Racca A, Calanni L, Vellone VG, et al. Efficacy and acceptability of long-term norethindrone acetate for the treatment of rectovaginal endometriosis. Eur J Obstet Gynecol Reprod Biol. 2017;213:4–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Fedele L, Arcaini L, Bianchi S, Baglioni A, Vercellini P. Comparison of cyproterone acetate and danazol in the treatment of pelvic pain associated with endometriosis. Obstet Gynecol. 1989;73(6):1000–4.PubMedGoogle Scholar
  32. 32.
    Scala C, Maggiore ULR, Remorgida V, Venturini PL, Ferrero S. Drug safety evaluation of desogestrel. Expert Opin Drug Saf. 2013;12(3):433–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Razzi S, Luisi S, Ferretti C, Calonaci F, Gabbanini M, Mazzini M, et al. Use of a progestogen only preparation containing desogestrel in the treatment of recurrent pelvic pain after conservative surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol. 2007;135(2):188–90.PubMedCrossRefGoogle Scholar
  34. 34.
    Morotti M, Remorgida V, Venturini PL, Ferrero S. Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study. Eur J Obstet Gynecol Reprod Biol. 2014;183:178–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Walch K, Unfried G, Huber J, Kurz C, van Trotsenburg M, Pernicka E, et al. Implanon versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic endometriosis—a pilot study. Contraception. 2009;79(1):29–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Telimaa S, Puolakka J, Ronnberg L, Kauppila A. Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol. 1987;1(1):13–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Telimaa S, Ronnberg L, Kauppila A. Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis after conservative surgery. Gynecol Endocrinol. 1987;1(4):363–71.PubMedCrossRefGoogle Scholar
  38. 38.
    Bergqvist A, Theorell T. Changes in quality of life after hormonal treatment of endometriosis. Acta Obstet Gynecol Scand. 2001;80(7):628–37.PubMedCrossRefGoogle Scholar
  39. 39.
    Harrison RF, Barry-Kinsella C. Efficacy of medroxyprogesterone treatment in infertile women with endometriosis: a prospective, randomized, placebo-controlled study. Fertil Steril. 2000;74(1):24–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Vercellini P, De Giorgi O, Oldani S, Cortesi I, Panazza S, Crosignani PG. Depot medroxyprogesterone acetate versus an oral contraceptive combined with very–low-dose danazol for long-term treatment of pelvic pain associated with endometriosis. Am J Obstet Gynecol. 1996;175(2):396–401.PubMedCrossRefGoogle Scholar
  41. 41.
    Wong AYK, Tang LCH, Chin RKH. Levonorgestrel-releasing intrauterine system (Mirena®) and Depot medroxyprogesterone acetate (Depoprovera) as long-term maintenance therapy for patients with moderate and severe endometriosis: A randomised controlled trial. Aust N Z J Obstet Gynaecol. 2010;50(3):273–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006;21(1):248–56.PubMedCrossRefGoogle Scholar
  43. 43.
    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. Fertil Steril. 2006;85(2):314–25.PubMedCrossRefGoogle Scholar
  44. 44.
    Curtis KM, Martins SL. Progestogen-only contraception and bone mineral density: a systematic review. Contraception. 2006;73(5):470–87.PubMedCrossRefGoogle Scholar
  45. 45.
    Guilbert ER, Brown JP, Kaunitz AM, Wagner MS, Berube J, Charbonneau L, et al. The use of depot–medroxyprogesterone acetate in contraception and its potential impact on skeletal health. Contraception. 2009;79(3):167–77.PubMedCrossRefGoogle Scholar
  46. 46.
    Vestergaard P, Rejnmark L, Mosekilde L. The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women. Contraception. 2008;78(6):459–64.PubMedCrossRefGoogle Scholar
  47. 47.
    Lanza LL, McQuay LJ, Rothman KJ, Bone HG, Kaunitz AM, Harel Z, et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstet Gynecol. 2013;121(3):593–600.PubMedCrossRefGoogle Scholar
  48. 48.
    Meier C, Brauchli YB, Jick SS, Kraenzlin ME, Meier CR. Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab. 2010;95(11):4909–16.PubMedCrossRefGoogle Scholar
  49. 49.
    The American College of Obstetricians and Gynecologist. Depot Medroxyprogesterone Acetate and Bone Efects. Committee Opinion. 2014. Accessed 26 May 2018.
  50. 50.
    Harada T, Taniguchi F. Dienogest: a new therapeutic agent for the treatment of endometriosis. Womens Health (Lond). 2010;6(1):27–35.CrossRefGoogle Scholar
  51. 51.
    Medicines Evaluation Board. PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board in the Netherlands Visanne, tablets, 2 mg Bayer BV. 2010. Accessed 26 May 2018.
  52. 52.
    Bizzarri N, Remorgida V, Maggiore ULR, Scala C, Tafi E, Ghirardi V, et al. Dienogest in the treatment of endometriosis. Expert Opin Pharmacother. 2014;15(13):1889–902.PubMedCrossRefGoogle Scholar
  53. 53.
    Andres Mde P, Lopes LA, Baracat EC, Podgaec S. Dienogest in the treatment of endometriosis: systematic review. Arch Gynecol Obstet. 2015;292(3):523–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Kitawaki J, Kusuki I, Yamanaka K, Suganuma I. Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol. 2011;157(2):212–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Lang J, Yu Q, Zhang S, Li H, Gude K, von Ludwig C, et al. Dienogest for treatment of endometriosis in chinese women: a placebo-controlled, randomized, double–blind phase 3 study. J Women Health (Larchmt). 2018;27(2):148–55.CrossRefGoogle Scholar
  56. 56.
    Morotti M, Sozzi F, Remorgida V, Venturini PL, Ferrero S. Dienogest in women with persistent endometriosis–related pelvic pain during norethisterone acetate treatment. Eur J Obstet Gynecol Reprod Biol. 2014;183:188–92.PubMedCrossRefGoogle Scholar
  57. 57.
    Maggiore ULR, Ferrero S, Candiani M, Somigliana E, Vigano P, Vercellini P. Bladder endometriosis: a systematic review of pathogenesis, diagnosis, treatment, impact on fertility, and risk of malignant transformation. Eur Urol. 2017;71(5):790–807.CrossRefGoogle Scholar
  58. 58.
    Angioni S, Nappi L, Pontis A, Sedda F, Luisi S, Mais V, et al. Dienogest. A possible conservative approach in bladder endometriosis. Results of a pilot study. Gynecol Endocrinol. 2015;31(5):406–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Leonardo-Pinto JP, Benetti-Pinto CL, Cursino K, Yela DA. Dienogest and deep infiltrating endometriosis: The remission of symptoms is not related to endometriosis nodule remission. Eur J Obstet Gynecol Reprod Biol. 2017;211:108–11.PubMedCrossRefGoogle Scholar
  60. 60.
    Vercellini P, Bracco B, Mosconi P, Roberto A, Alberico D, Dhouha D, et al. Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study. Fertil Steril. 2016;105(3):734–743.e3.PubMedCrossRefGoogle Scholar
  61. 61.
    Lee DY, Lee JY, Seo JW, Yoon BK, Choi DS. Gonadotropin-releasing hormone agonist with add–back treatment is as effective and tolerable as dienogest in preventing pain recurrence after laparoscopic surgery for endometriosis. Arch Gynecol Obstet. 2016;294(6):1257–63.PubMedCrossRefGoogle Scholar
  62. 62.
    Momoeda M, Harada T, Terakawa N, Aso T, Fukunaga M, Hagino H, et al. Long–term use of dienogest for the treatment of endometriosis. J Obstetr Gynaecol Res. 2009;35(6):1069–76.CrossRefGoogle Scholar
  63. 63.
    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. Hum Reprod. 2010;25(3):633–41.PubMedCrossRefGoogle Scholar
  64. 64.
    Luukkainen T, Toivonen J. Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties. Contraception. 1995;52(5):269–76.PubMedCrossRefGoogle Scholar
  65. 65.
    Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril. 2001;75(3):485–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa e Silva JC, Hassan D, 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. Hum Reprod. 2005;20(7):1993–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Lan S, Ling L, Jianhong Z, Xijing J, Lihui W. Analysis of the levonorgestrel-releasing intrauterine system in women with endometriosis. J Int Med Res. 2013;41(3):548–58.PubMedCrossRefGoogle Scholar
  68. 68.
    Lockhat FB, Emembolu JO, Konje JC. The efficacy, side–effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intra–uterine administered progestogen (levonorgestrel): a 3 year follow-up. Hum Reprod. 2005;20(3):789–93.PubMedCrossRefGoogle Scholar
  69. 69.
    Abu Hashim H. Gonadotrophin-releasing hormone analogues and endometriosis: current strategies and new insights. Gynecol Endocrinol. 2012;28(4):314–21.CrossRefGoogle Scholar
  70. 70.
    Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2010;12:CD008475.Google Scholar
  71. 71.
    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. Fertil Steril. 1993;59(3):516–21.PubMedCrossRefGoogle Scholar
  72. 72.
    Bergqvist A, Bergh T, Hogstrom L, Mattsson S, Nordenskjold F, Rasmussen C. Effects of triptorelin versus placebo on the symptoms of endometriosis. Fertil Steril. 1998;69(4):702–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Dlugi AM, Miller JD, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertil Steril. 1990;54(3):419–27.PubMedCrossRefGoogle Scholar
  74. 74.
    Miller JD. Leuprolide acetate for the treatment of endometriosis. Prog Clin Biol Res. 1990;323:337–41.PubMedGoogle Scholar
  75. 75.
    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. Am J Obstet Gynecol. 2000;182(6):1483–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis—a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91(3):675–81.PubMedCrossRefGoogle Scholar
  77. 77.
    Ferreira RA, Vieira CS, Rosa ESJC, Rosa-e-Silva AC, Nogueira AA, Ferriani RA. Effects of the levonorgestrel-releasing intrauterine system on cardiovascular risk markers in patients with endometriosis: a comparative study with the GnRH analogue. Contraception. 2010;81(2):117–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Bayoglu Tekin Y, Dilbaz B, Altinbas SK, Dilbaz S. Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue. Fertil Steril. 2011;95(2):492–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of post–surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod. 2004;19(1):160–7.PubMedCrossRefGoogle Scholar
  80. 80.
    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. Prog Clin Biol Res. 1986;225:211–25.PubMedGoogle Scholar
  81. 81.
    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. N Engl J Med. 1988;318(8):485–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Adamson GD, Kwei L, Edgren RA. Pain of endometriosis: effects of nafarelin and danazol therapy. Int J Fertil Menopausal Stud. 1994;39(4):215–7.PubMedGoogle Scholar
  83. 83.
    Hornstein MD, Yuzpe AA, Burry KA, Heinrichs LR, Buttram VL Jr, Orwoll ES. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertil Steril. 1995;63(5):955–62.PubMedCrossRefGoogle Scholar
  84. 84.
    Lemay A, Maheux R, Huot C, Blanchet J, Faure N. Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis. Am J Obstet Gynecol. 1988;158(2):233–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Dmowski WP, Radwanska E, Binor Z, Tummon I, Pepping P. Ovarian suppression induced with Buserelin or danazol in the management of endometriosis: a randomized, comparative study. Fertil Steril. 1989;51(3):395–400.PubMedCrossRefGoogle Scholar
  86. 86.
    Dawood MY, Spellacy WN, Dmowski WP, Gambrell RD Jr, Greenblatt RB, Girard Y, et al. A comparison of the efficacy and safety of buserelin vs danazol in the treatment of endometriosis. Protocol 310 Study Group. Prog Clin Biol Res. 1990;323:253–67.PubMedGoogle Scholar
  87. 87.
    Agarwal SK, Hamrang C, Henzl MR, Judd HL. Nafarelin vs. leuprolide acetate depot for endometriosis. Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group. J Reprod Med. 1997;42(7):413–23.PubMedGoogle Scholar
  88. 88.
    Donaldson VH. Danazol. Am J Med. 1989;87(3N):49N–55N.PubMedGoogle Scholar
  89. 89.
    Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results. Am J Obstet Gynecol. 1992;167(5):1367–71.PubMedCrossRefGoogle Scholar
  90. 90.
    Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB. Gestrinone versus danazol in the treatment of endometriosis. Fertil Steril. 1989;51(5):781–5.PubMedCrossRefGoogle Scholar
  91. 91.
    Wong AY, Tang L. An open and randomized study comparing the efficacy of standard danazol and modified triptorelin regimens for postoperative disease management of moderate to severe endometriosis. Fertil Steril. 2004;81(6):1522–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Ferrero S, Remorgida V, Maganza C, Venturini PL, Salvatore S, Papaleo E, et al. Aromatase and endometriosis: estrogens play a role. Ann N Y Acad Sci. 2014;1317:17–23.PubMedCrossRefGoogle Scholar
  93. 93.
    Ferrero S, Venturini PL, Ragni N, Camerini G, Remorgida V. Pharmacological treatment of endometriosis: experience with aromatase inhibitors. Drugs. 2009;69(8):943–52.PubMedCrossRefGoogle Scholar
  94. 94.
    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. Reprod Biol Endocrinol. 2011;9:88.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Alborzi S, Hamedi B, Omidvar A, Dehbashi S, Alborzi S, Alborzi M. A comparison of the effect of short-term aromatase inhibitor (letrozole) and GnRH agonist (triptorelin) versus case control on pregnancy rate and symptom and sign recurrence after laparoscopic treatment of endometriosis. Arch Gynecol Obstet. 2011;284(1):105–10.PubMedCrossRefGoogle Scholar
  96. 96.
    Seal SL, Kamilya G, Mukherji J, De A, Ghosh D, Majhi AK. Aromatase inhibitors in recurrent ovarian endometriomas: Report of five cases with literature review. Fertil Steril. 2011;95(1):291.e15–.e18.CrossRefGoogle Scholar
  97. 97.
    Cetel NS, Rivier J, Vale W, Yen SS. The dynamics of gonadotropin inhibition in women induced by an antagonistic analog of gonadotropin-releasing hormone. J Clin Endocrinol Metab. 1983;57(1):62–5.PubMedCrossRefGoogle Scholar
  98. 98.
    Finas D, Hornung D, Diedrich K, Schultze-Mosgau A. Cetrorelix in the treatment of female infertility and endometriosis. Expert Opin Pharmacother. 2006;7(15):2155–68.PubMedCrossRefGoogle Scholar
  99. 99.
    Taniguchi F, Higaki H, Azuma Y, Deura I, Iwabe T, Harada T, et al. Gonadotropin-releasing hormone analogues reduce the proliferation of endometrial stromal cells but not endometriotic cells. Gynecol Obstet Invest. 2013;75(1):9–15.PubMedCrossRefGoogle Scholar
  100. 100.
    Altintas D, Kokcu A, Tosun M, Cetinkaya MB, Kandemir B. Comparison of the effects of cetrorelix, a GnRH antagonist, and leuprolide, a GnRH agonist, on experimental endometriosis. J Obstet Gynaecol Res. 2008;34(6):1014–9.PubMedGoogle Scholar
  101. 101.
    Kupker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online. 2002;5(1):12–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Melis GB, Neri M, Corda V, Malune ME, Piras B, Pirarba S, et al. Overview of elagolix for the treatment of endometriosis. Expert Opin Drug Metab Toxicol. 2016;12(5):581–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Struthers RS, Chen T, Campbell B, Jimenez R, Pan H, Yen SS, et al. Suppression of serum luteinizing hormone in postmenopausal women by an orally administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor (NBI–42902). J Clin Endocrinol Metab. 2006;91(10):3903–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, et al. Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study. Reprod Sci. 2014;21(3):363–71.PubMedCrossRefGoogle Scholar
  105. 105.
    Carr B, Dmowski WP, O’Brien C, Jiang P, Burke J, Jimenez R, et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci. 2014;21(11):1341–51.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377(1):28–40.PubMedCrossRefGoogle Scholar
  107. 107.
    Nakata D, Masaki T, Tanaka A, Yoshimatsu M, Akinaga Y, Asada M, et al. Suppression of the hypothalamic–pituitary–gonadal axis by TAK–385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock–in mice. Eur J Pharmacol. 2014;723:167–74.PubMedCrossRefGoogle Scholar
  108. 108.
    Osuga Y, Seki Y, Tanimoto M, Kusumoto T, Kodou K, Terakawa N, editors. Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, in women with endometriosis (EM)-associated pain: Phase 2 safety and efficacy 24–week results. In: 19th European Congress of Endocrinology; 2017; Lisbon, Portugal: Bioscientifica. 2017.Google Scholar
  109. 109.
    Schweppe KW. Current place of progestins in the treatment of endometriosis–related complaints. Gynecol Endocrinol. 2001;15(Suppl 6):22–8.PubMedCrossRefGoogle Scholar
  110. 110.
    Hornstein MD. An oral GnRH antagonist for endometriosis—a new drug for an old disease. N Engl J Med. 2017;377(1):81–3.PubMedCrossRefGoogle Scholar
  111. 111.
    Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update. 2007;13(4):395–404.PubMedCrossRefGoogle Scholar
  112. 112.
    Wu B, Yang Z, Tobe RG, Wang Y. Medical therapy for preventing recurrent endometriosis after conservative surgery: a cost–effectiveness analysis. BJOG Int J Obstetr Gynaecol. 2018;125(4):469–77.CrossRefGoogle Scholar
  113. 113.
    Barra F, Scala C, Mais V, Guerriero S, Ferrero S. Investigational drugs for the treatment of endometriosis, an update on recent developments. Expert Opin Investig Drugs. 2018;27(5):445–58.PubMedCrossRefGoogle Scholar
  114. 114.
    Cosson M, Querleu D, Donnez J, Madelenat P, Konincks P, Audebert A, et al. Dienogest is as effective as triptorelin in the treatment of endometriosis after laparoscopic surgery: results of a prospective, multicenter, randomized study. Fertil Steril. 2002;77(4):684–92.PubMedCrossRefGoogle Scholar
  115. 115.
    Takaesu Y, Nishi H, Kojima J, Sasaki T, Nagamitsu Y, Kato R, et al. Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis. J Obstet Gynaecol Res. 2016;42(9):1152–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Academic Unit of Obstetrics and GynecologyOspedale Policlinico San MartinoGenoaItaly
  2. 2.Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI)University of GenoaGenoaItaly

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