Pathogenesis of Endometriosis: Progesterone Resistance in Women with Endometriosis

Research has shown that endometriosis is an estrogen-dependent disease. Dysregulation of steroid action appears to be one of the key pathogenetic factors in altered cellular function in the endometrium as well as in lesions in women suffering from endometriosis. The normal hormonal balance and homeostasis are disturbed, leading to an increased estrogen activity and progesterone resistance. In particular, an increased activity of the enzyme aromatase and a decreased expression of 17β-hydroxysteroid-dehydrogenase (17β-HSD-2) are main characteristics of endometriosis. This results in an enhanced bioavailability of estradiol and further stimulation of aromatase. Together with a reduced number of the progesterone receptors PR-A and PR-B, increased cellular estradiol levels, and altered signaling pathways, this causes relative progesterone resistance – one of the most important mechanisms in the pathogenesis of the enigmatic disease. What is more, resistance to progesterone is also linked to failure of long-term treatment for pain and infertility. Consequently, women often suffer from high recurrence rates following surgery and medical therapies. This provides evidence for the need to develop new modalities with long-term efficacy to possibly overcome progesterone resistance. In order to develop novel approaches, however, detailed understanding of the mechanisms of dysregulation in the endometrium and endometriotic lesions in women diagnosed with endometriosis is required. Access this chapter Tax calculation will be finalised at checkout Purchases are for personal use only Similar content being viewed by others

Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. Endometriosis. Nat Rev Dis Primers. 2018;4(1) https://doi.org/10.1038/s41572-018-0008-5. Karim AK, Shafiee MN, Abd Aziz NH, Omar MH, Abdul Ghani NA, Lim PS, Md Zin RR, Mokhtar N. Reviewing the role of progesterone therapy in endometriosis. Gynecol Endocrinol. 2019;35(1):10–6. https://doi.org/10.1080/09513590.2018.1490404. Marquardt RM, Kim TH, Shin JH, Jeong JW. Progesterone and estrogen signaling in the endometrium: what goes wrong in endometriosis? Int J Mol Sci. 2019;20(15) https://doi.org/10.3390/ijms20153822. Bulun SE, Cheng YH, Pavone ME, Xue Q, Attar E, Trukhacheva E, Tokunaga H, Utsunomiya H, Yin P, Luo X, others. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):36–43. https://doi.org/10.1055/s-0029-1242991.Estrogen. Chen H, Malentacchi F, Fambrini M, Harrath AH, Huang H, Petraglia F. Epigenetics of estrogen and progesterone receptors in endometriosis. Reprod Sci. 2020;27(11):1967–74. https://doi.org/10.1007/s43032-020-00226-2. Yotova I, Hsu E, Do C, Gaba A, Szabolcs M, Dekan S, Kenner L, Wenzl R, Tycko B. Epigenetic alterations affecting transcription factors and signaling pathways in stromal cells of endometriosis. PLoS ONE. 2017;12(1) https://doi.org/10.1371/journal.pone.0170859. Houshdaran S, Oke AB, Fung JC, Vo KC, Nezhat C, Giudice LC. Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis. PLoS Genet. 2020;16(6) https://doi.org/10.1371/journal.pgen.1008601. Szukiewicz D, Stangret A, Ruiz-Ruiz C, Olivares EG, Soriţău O, Suşman S, Szewczyk G. Estrogen- and progesterone (P4)-mediated epigenetic modifications of endometrial stromal cells (EnSCs) and/or mesenchymal stem/stromal cells (MSCs) in the etiopathogenesis of endometriosis. Stem Cell Rev Rep. 2021; https://doi.org/10.1007/s12015-020-10115-5. Joshi NR, Miyadahira EH, Afshar Y, Jeong JW, Young SL, Lessey BA, Serafini PC, Fazleabas AT. Progesterone resistance in endometriosis is modulated by the altered expression of MicroRNA-29c and FKBP4. J Clin Endocrinol Metab. 2017;102(1):141–9. https://doi.org/10.1210/jc.2016-2076. Krikun G, Mor G, Alvero A, Guller S, Schatz F, Sapi E, Rahman M, Caze R, Qumsiyeh M, Lockwood CJ. A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology. 2004;145(5):2291–6. https://doi.org/10.1210/en.2003-1606. Bulun SE, Monsivais D, Kakinuma T, Furukawa Y, Bernardi L, Pavone ME, Dyson M. Molecular biology of endometriosis: from aromatase to genomic abnormalities. Semin Reprod Med. 2015;33(3):220–4. https://doi.org/10.1055/s-0035-1554053. Epub 2015 Jun 2. Morotti M, Venturini PL, Biscaldi E, 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. 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. 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. Lang J, Yu Q, Zhang S, et al. Dienogest for treatment of endometriosis in Chinese women: a placebo-controlled, randomized, double-blind phase 3 study. J Women Health (2002). 2018;27(2):148–55. Yu Q, Zhang S, Li H, et al. Dienogest for treatment of endometriosis in women: a 28-week, open-label, extension study. J Women Health (2002). 2019;28(2):170–7. Carr B, Dmowski WP, O’Brien C, et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci (Thousand Oaks, CA). 2014;21(11):1341–51. Chen YJ, Hsu TF, Huang BS, Tsai HW, Chang YH, Wang PH. Postoperative maintenance levonorgestrel-releasing intrauterine system and endometrioma recurrence: a randomized controlled study. Am J Obstet Gynecol. 2017;216(6):582.e581–9. Flores VA, Vanhie A, Dang T, Taylor HS. Progesterone receptor status predicts response to progestin therapy in endometriosis. J Clin Endocrinol Metab. 2018;103(12):4561–8. https://doi.org/10.1210/jc.2018-01227. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet Gynecol Scand. 2017;96(6):623–32. https://doi.org/10.1111/aogs.13156. Reis FM, Coutinho LM, Vannuccini S, Batteux F, Chapron C, Petraglia F. Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure. Hum Reprod Update. 2020;26(4):565–85. https://doi.org/10.1093/humupd/dmaa009. Brown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev. 2018;2018(5) https://doi.org/10.1002/14651858.CD001019.pub3. Lete I, Mendoza N, de la Viuda E, Carmona F. Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. Eur J Obstet Gynecol Reprod Biol. 2018;228:221–4. https://doi.org/10.1016/j.ejogrb.2018.07.002. Forte A, Cipollaro M, Galderisi U. Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic perspectives. Clin Sci. 2014;126(2):123–38. https://doi.org/10.1042/CS20130099. Moggio A, Pittatore G, Cassoni P, Marchino GL, Revelli A, Bussolati B. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6):1521–1530.e2. https://doi.org/10.1016/j.fertnstert.2012.08.003. Author information Authors and Affiliations Corresponding author Editor information Editors and Affiliations Rights and permissions Copyright information © 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG About this chapter Cite this chapter Kiesel, L., Vogel, M., Le, Q.K., Schäfer, S.D. (2022). Pathogenesis of Endometriosis: Progesterone Resistance in Women with Endometriosis. In: Oral, E. (eds) Endometriosis and Adenomyosis. Springer, Cham. https://doi.org/10.1007/978-3-030-97236-3_7 Download citation DOI: https://doi.org/10.1007/978-3-030-97236-3_7 Published: Publisher Name: Springer, Cham Print ISBN: 978-3-030-97235-6 Online ISBN: 978-3-030-97236-3 eBook Packages: MedicineMedicine (R0)