Investigational Medical Therapies for Endometriosis: Current Data and Future Trends

Abstract

Current mainstays of medical therapy for endometriosis preclude fertility or may have unwanted side effects. Therefore, research has been underway to find alternatives to current options which may be applied to future medical treatment. The focus of this review is that of investigational hormonal and nonhormonal medical therapies based on in vitro and in vivo animal models of endometriosis as well as in human endometrial and endometriotic cells in vitro. Assessment of the safety and efficacy of such novel medical treatments have been, and continue to be, necessary prior to clinical trials.

Keywords

endometriosis - GnRH antagonist - aromatase inhibitor - TNFα inhibitor - VEGF

• References

• 1 Mihalyi A, Simsa P, Mutinda KC, Meuleman C, Mwenda JM, D'Hooghe TM. Emerging drugs in endometriosis. Expert Opin Emerg Drugs 2006; 11 (03) 503-524
• 2 Horvath JE, Toller GL, Schally AV, Bajo AM, Groot K. Effect of long-term treatment with low doses of the LHRH antagonist Cetrorelix on pituitary receptors for LHRH and gonadal axis in male and female rats. Proc Natl Acad Sci U S A 2004; 101 (14) 4996-5001
• 3 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 (06) 1014-1019
• 4 Kim SM, Yoo T, Lee SY. , et al. Effect of SKI2670, a novel, orally active, non-peptide GnRH antagonist, on hypothalamic-pituitary-gonadal axis. Life Sci 2015; 139: 166-174
• 5 Lindsay SF, Luciano DE, Luciano AA. Emerging therapy for endometriosis. Expert Opin Emerg Drugs 2015; 20 (03) 449-461
• 6 Ezzati M, Carr BR. Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain. Womens Health (Lond) 2015; 11 (01) 19-28
• 7 Taylor HS, Giudice LC, Lessey BA. , et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med 2017; [Epub ahead of print]
• 8 Noble LS, Simpson ER, Johns A, Bulun SE. Aromatase expression in endometriosis. J Clin Endocrinol Metab 1996; 81 (01) 174-179
• 9 Heilier JF, Donnez O, Van Kerckhove V, Lison D, Donnez J. Expression of aromatase (P450 aromatase/CYP19) in peritoneal and ovarian endometriotic tissues and deep endometriotic (adenomyotic) nodules of the rectovaginal septum. Fertil Steril 2006; 85 (05) 1516-1518
• 10 Badawy SZ, Brown S, Kaufman L, Wojtowycz MA. Aromatase inhibitor (anastrozole) affects growth of endometrioma cells in culture. Eur J Obstet Gynecol Reprod Biol 2015; 188: 45-50
• 11 Lu X, Wu Y, Gao XH, Wang YW, Wang L, Sun XX. Effect of letrozole on estradiol production and P450 aromatase messenger RNA expression of cultured luteinized granulosa cells from women with and without endometriosis. Fertil Steril 2012; 98 (01) 131-135
• 12 Ceyhan ST, Onguru O, Fidan U. , et al. Comparison of aromatase inhibitor (letrozole) and immunomodulators (infliximab and etanercept) on the regression of endometriotic implants in a rat model. Eur J Obstet Gynecol Reprod Biol 2011; 154 (01) 100-104
• 13 Bilotas M, Meresman G, Stella I, Sueldo C, Barañao RI. Effect of aromatase inhibitors on ectopic endometrial growth and peritoneal environment in a mouse model of endometriosis. Fertil Steril 2010; 93 (08) 2513-2518
• 14 Olivares CN, Bilotas MA, Ricci AG, Barañao RI, Meresman GF. Anastrozole and celecoxib for endometriosis treatment, good to keep them apart?. Reproduction 2013; 145 (02) 119-126
• 15 Langoi D, Pavone ME, Gurates B, Chai D, Fazleabas A, Bulun SE. Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons. Fertil Steril 2013; 99 (03) 656-662.e3
• 16 Rotgeri A, Korolainen H, Sundholm O. , et al. Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys. Hum Reprod 2015; 30 (02) 308-314
• 17 Nawathe A, Patwardhan S, Yates D, Harrison GR, Khan KS. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG 2008; 115 (07) 818-822
• 18 Ferrero S, Gillott DJ, Venturini PL, Remorgida V. Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review. Reprod Biol Endocrinol 2011; 9: 89
• 19 Gomes MK, Rosa-e-Silva JC, Garcia SB. , et al. Effects of the levonorgestrel-releasing intrauterine system on cell proliferation, Fas expression and steroid receptors in endometriosis lesions and normal endometrium. Hum Reprod 2009; 24 (11) 2736-2745
• 20 Maruo T, Laoag-Fernandez JB, Pakarinen P, Murakoshi H, Spitz IM, Johansson E. Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium. Hum Reprod 2001; 16 (10) 2103-2108
• 21 Abou-Setta AM, Houston B, Al-Inany HG, Farquhar C. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev 2013; 1 (01) CD005072
• 22 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 (02) 492-496
• 23 Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, Techatraisak K, Indhavivadhana S, Leerasiri P. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol 2012; 119 (03) 519-526
• 24 Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003; 80 (02) 305-309
• 25 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 (03) 789-793
• 26 Yamanaka K, Xu B, Suganuma I. , et al. Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E₂ production in human endometriotic stromal cells in spheroid culture. Fertil Steril 2012; 97 (02) 477-482
• 27 Shimizu Y, Mita S, Takeuchi T, Notsu T, Mizuguchi K, Kyo S. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids 2011; 76 (1-2): 60-67
• 28 Mita S, Shimizu Y, Notsu T, Imada K, Kyo S. Dienogest inhibits Toll-like receptor 4 expression induced by costimulation of lipopolysaccharide and high-mobility group box 1 in endometrial epithelial cells. Fertil Steril 2011; 96 (06) 1485-1489.e4
• 29 Allhorn S, Böing C, Koch AA, Kimmig R, Gashaw I. TLR3 and TLR4 expression in healthy and diseased human endometrium. Reprod Biol Endocrinol 2008; 6: 40
• 30 Grandi G, Mueller M, Bersinger NA, Cagnacci A, Volpe A, McKinnon B. Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res 2016; 65 (03) 183-192
• 31 Andres MdeP, Lopes LA, Baracat EC, Podgaec S. Dienogest in the treatment of endometriosis: systematic review. Arch Gynecol Obstet 2015; 292 (03) 523-529
• 32 Surrey ES, Halme J. Direct effects of medroxyprogesterone acetate, danazol, and leuprolide acetate on endometrial stromal cell proliferation in vitro. Fertil Steril 1992; 58 (02) 273-278
• 33 Tanaka T, Umesaki N. Danazol enhances Fas-mediated apoptosis in human endometrial epithelial cells within normal physiology. Int J Mol Med 2009; 23 (02) 237-243
• 34 Maia Jr H, Casoy J, Valente Filho J. Is aromatase expression in the endometrium the cause of endometriosis and related infertility?. Gynecol Endocrinol 2009; 25 (04) 253-257
• 35 Ishihara H, Kitawaki J, Kado N, Koshiba H, Fushiki S, Honjo H. Gonadotropin-releasing hormone agonist and danazol normalize aromatase cytochrome P450 expression in eutopic endometrium from women with endometriosis, adenomyosis, or leiomyomas. Fertil Steril 2003; 79 (Suppl. 01) 735-742
• 36 Godin R, Marcoux V. Vaginally administered danazol: an over-looked option in the treatment of rectovaginal endometriosis?. J Obstet Gynaecol Can 2015; 37 (12) 1098-1103
• 37 Igarashi M, Iizuka M, Abe Y, Ibuki Y. Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis. Hum Reprod 1998; 13 (07) 1952-1956
• 38 Buelke-Sam J, Bryant HU, Francis PC. The selective estrogen receptor modulator, raloxifene: an overview of nonclinical pharmacology and reproductive and developmental testing. Reprod Toxicol 1998; 12 (03) 217-221
• 39 Naqvi H, Sakr S, Presti T, Krikun G, Komm B, Taylor HS. Treatment with bazedoxifene and conjugated estrogens results in regression of endometriosis in a murine model. Biol Reprod 2014; 90 (06) 121
• 40 Kulak Jr J, Fischer C, Komm B, Taylor HS. Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. Endocrinology 2011; 152 (08) 3226-3232
• 41 Altintas D, Kokcu A, Kandemir B, Tosun M, Cetinkaya MB. Comparison of the effects of raloxifene and anastrozole on experimental endometriosis. Eur J Obstet Gynecol Reprod Biol 2010; 150 (01) 84-87
• 42 Guo SW, Olive DL. Two unsuccessful clinical trials on endometriosis and a few lessons learned. Gynecol Obstet Invest 2007; 64 (01) 24-35
• 43 Tjaden B, Galetto D, Woodruff JD, Rock JA. Time-related effects of RU486 treatment in experimentally induced endometriosis in the rat. Fertil Steril 1993; 59 (02) 437-440
• 44 Wu Y, Guo SW. Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780. Gynecol Obstet Invest 2006; 62 (04) 193-205
• 45 Bouchard P. Selective progesterone receptor modulators: a class with multiple actions and applications in reproductive endocrinology, and gynecology. Gynecol Endocrinol 2014; 30 (10) 683-684
• 46 Chwalisz K, Garg R, Brenner R, Slayden O, Winkel C, Elger W. Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs). Reprod Biol Endocrinol 2006; 4 (Suppl. 01) S8
• 47 Brenner RM, Slayden OD, Nath A, Tsong YY, Sitruk-Ware R. Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques. Contraception 2010; 81 (04) 336-342
• 48 Gopalkrishnan K, Katkam RR, Sachdeva G, Kholkute SD, Padwal V, Puri CP. Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies. Biol Reprod 2003; 68 (06) 1959-1967
• 49 Zhang Z, Lundeen SG, Slayden O. , et al. In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910. Ernst Schering Found Symp Proc 2007; [phone]
• 50 Moe BG, Vereide AB, Orbo A, Sager G. High concentrations of progesterone and mifepristone mutually reinforce cell cycle retardation and induction of apoptosis. Anticancer Res 2009; 29 (04) 1053-1058
• 51 Gori I, Pellegrini C, Staedler D, Russell R, Jan C, Canny GO. Tumor necrosis factor-α activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor α. Mol Cell Endocrinol 2011; 345 (1-2): 27-37
• 52 Altan ZM, Denis D, Kagan D, Grund EM, Palmer SS, Nataraja SG. A long-acting tumor necrosis factor alpha-binding protein demonstrates activity in both in vitro and in vivo models of endometriosis. J Pharmacol Exp Ther 2010; 334 (02) 460-466
• 53 D'Antonio M, Martelli F, Peano S, Papoian R, Borrelli F. Ability of recombinant human TNF binding protein-1 (r-hTBP-1) to inhibit the development of experimentally-induced endometriosis in rats. J Reprod Immunol 2000; 48 (02) 81-98
• 54 Yildirim G, Attar R, Ficicioglu C, Karateke A, Ozkan F, Yesildaglar N. Etanercept causes regression of endometriotic implants in a rat model. Arch Gynecol Obstet 2011; 283 (06) 1297-1302
• 55 Kurt RK, Pinar N, Karateke A. , et al. Protective effects of colchicine in an experimental rat endometriosis model: histopathological evaluation and assessment of TNF-α levels. Reprod Sci 2015; 22 (02) 258-263
• 56 Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, Propst AM. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril 2004; 81 (Suppl. 01) 775-779
• 57 D'Hooghe TM, Nugent NP, Cuneo S. , et al. Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study. Biol Reprod 2006; 74 (01) 131-136
• 58 Falconer H, Mwenda JM, Chai DC. , et al. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod 2006; 21 (07) 1856-1862
• 59 Chen YJ, Wu HH, Liau WT. , et al. A tumor necrosis factor-α inhibitor reduces the embryotoxic effects of endometriotic peritoneal fluid. Fertil Steril 2013; 100 (05) 1476-1485
• 60 Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003; 138 (10) 807-811 Review
• 61 Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46 (12) 3151-3158
• 62 Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. ; BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48 (08) 2122-2127
• 63 Kyama CM, Mihalyi A, Simsa P. , et al. Non-steroidal targets in the diagnosis and treatment of endometriosis. Curr Med Chem 2008; 15 (10) 1006-1017
• 64 Gargett CE, Rogers PA. Human endometrial angiogenesis. Reproduction 2001; 121 (02) 181-186
• 65 Shifren JL, Tseng JF, Zaloudek CJ. , et al. Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab 1996; 81 (08) 3112-3118
• 66 Laschke MW, Menger MD. Anti-angiogenic treatment strategies for the therapy of endometriosis. Hum Reprod Update 2012; 18 (06) 682-702
• 67 Liu F, Wang L, Zhang XX. , et al. Vascular endothelial growth factor receptor-2 inhibitor cediranib causes regression of endometriotic lesions in a rat model. Int J Clin Exp Pathol 2015; 8 (02) 1165-1174
• 68 Yildiz C, Kacan T, Akkar OB. , et al. Effects of pazopanib, sunitinib, and sorafenib, anti-VEGF agents, on the growth of experimental endometriosis in rats. Reprod Sci 2015; 22 (11) 1445-1451
• 69 Song WW, Lu H, Hou WJ. , et al. Expression of vascular endothelial growth factor C and anti-angiogenesis therapy in endometriosis. Int J Clin Exp Pathol 2014; 7 (11) 7752-7759
• 70 Sevket O, Sevket A, Buyukpinarbasili N. , et al. The effects of ranibizumab on surgically induced endometriosis in a rat model: a preliminary study. Reprod Sci 2013; 20 (10) 1224-1229
• 71 Ricci AG, Olivares CN, Bilotas MA, Meresman GF, Barañao RI. Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis. Reprod Sci 2011; 18 (07) 614-622
• 72 Jiang HQ, Li YL, Zou J. Effect of recombinant human endostatin on endometriosis in mice. Chin Med J (Engl) 2007; 120 (14) 1241-1246
• 73 Ren XU, Wang Y, Xu G, Dai L. Effect of rapamycin on endometriosis in mice. Exp Ther Med 2016; 12 (01) 101-106
• 74 Laschke MW, Elitzsch A, Scheuer C, Holstein JH, Vollmar B, Menger MD. Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation. Br J Pharmacol 2006; 149 (02) 137-144
• 75 Nap AW, Griffioen AW, Dunselman GA. , et al. Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab 2004; 89 (03) 1089-1095
• 76 Novella-Maestre E, Carda C, Noguera I. , et al. Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis. Hum Reprod 2009; 24 (05) 1025-1035
• 77 Liu S, Xin X, Hua T. , et al. Efficacy of anti-VEGF/VEGFR agents on animal models of endometriosis: a systematic review and meta-analysis. PLoS One 2016; 11 (11) e0166658
• 78 Becker CM, Sampson DA, Rupnick MA. , et al. Endostatin inhibits the growth of endometriotic lesions but does not affect fertility. Fertil Steril 2005; 84 (Suppl. 02) 1144-1155
• 79 Ozer H, Boztosun A, Açmaz G, Atilgan R, Akkar OB, Kosar MI. The efficacy of bevacizumab, sorafenib, and retinoic acid on rat endometriosis model. Reprod Sci 2013; 20 (01) 26-32
• 80 Pritts EA, Zhao D, Ricke E, Waite L, Taylor RN. PPAR-gamma decreases endometrial stromal cell transcription and translation of RANTES in vitro. J Clin Endocrinol Metab 2002; 87 (04) 1841-1844
• 81 Wanichkul T, Han S, Huang RP, Sidell N. Cytokine regulation by peroxisome proliferator-activated receptor gamma in human endometrial cells. Fertil Steril 2003; 79 (Suppl. 01) 763-769
• 82 Kavoussi SK, Witz CA, Binkley PA, Nair AS, Lebovic DI. Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion. Mol Hum Reprod 2009; 15 (10) 687-692
• 83 Lebovic DI, Kavoussi SK, Lee J, Banu SK, Arosh JA. PPARγ activation inhibits growth and survival of human endometriotic cells by suppressing estrogen biosynthesis and PGE2 signaling. Endocrinology 2013; 154 (12) 4803-4813
• 84 Lebovic DI, Kir M, Casey CL. Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril 2004; 82 (Suppl. 03) 1008-1013
• 85 Demirturk F, Aytan H, Caliskan AC, Aytan P, Koseoglu DR. Effect of peroxisome proliferator-activated receptor-gamma agonist rosiglitazone on the induction of endometriosis in an experimental rat model. J Soc Gynecol Investig 2006; 13 (01) 58-62
• 86 Klinkner DB, Lim HJ, Strawn Jr EY, Oldham KT, Sander TL. An in vivo murine model of rosiglitazone use in pregnancy. Fertil Steril 2006; 86 (4, Suppl): 1074-1079
• 87 Lebovic DI, Mwenda JM, Chai DC. , et al. PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: a prospective, randomized, placebo- and drug-controlled study. Fertil Steril 2007; 88 (4, Suppl): 1108-1119
• 88 Oner G, Ozcelik B, Ozgun MT, Serin IS, Ozturk F, Basbug M. The effects of metformin and letrozole on endometriosis and comparison of the two treatment agents in a rat model. Hum Reprod 2010; 25 (04) 932-937
• 89 Kiykac Altinbas S, Tapisiz OL, Cavkaytar S, Simsek G, Oguztuzun S, Goktolga U. Is montelukast effective in regression of endometrial implants in an experimentally induced endometriosis model in rats?. Eur J Obstet Gynecol Reprod Biol 2015; 184: 7-12