Factors Affecting Hormonal Therapy Ineffectiveness and Discontinuation due to Adverse Effects in Patients with Endometriosis-Associated Pain

Endometriosis contributes to 5–21% of hospital admissions for pelvic pain. While hormonal therapies are pivotal in managing endometriosis-related pain, no single hormonal treatment suits all patients. We aimed to assess the effectiveness and tolerability of hormonal therapies and factors influencing response in endometriosis-associated pain treatment. Additionally, to investigate adjuvant neuromodulatory drug usage in patients who have used hormonal therapy. This cross-sectional study examined endometriosis patients undergoing hormonal therapy for pelvic pain at a tertiary referral centre for endometriosis and chronic pelvic pain (CPP). We assessed the proportion of patients reporting ineffectiveness of hormonal therapy and rates of discontinuation attributed to side effects. We evaluated factors related to treatment ineffectiveness and discontinuation due to side effects. Lastly, we determined the rates of adjuvant neuromodulatory drug use among patients who used hormonal therapy. 1011 patients were included in the study. Most hormonal therapies’ ineffectiveness was related to worse CPP (P < .05). Cul-de-sac obliteration was correlated with better response to cyclic CHCs, DNG, and GnRH agonist (OR = 0.55, 95% CI [0.36 – 0.84]; OR = 0.53, 95% CI [0.29 – 0.98]; OR = 0.26, 95% CI [0.14 – 0.91], respectively). Adjuvant neuromodulatory drugs were more frequently utilized by patients who found hormone therapy ineffective except for those who used norethisterone acetate (NETA). Endometriosis pain is associated with a high chance of failed hormonal therapy. Cul-de-sac obliteration correlated with improved hormonal therapy response, highlighting the multifactorial influence on treatment outcomes. Patients who found hormone therapy ineffective tended to use adjuvant neuromodulatory drugs more frequently. Similar content being viewed by others Data Availability Request for data collected for the study can be made to the corresponding author and will be considered on an individual basis in accordance with the internal regulations of the health authority.

Ball E, Khan KS. Recent advances in understanding and managing chronic pelvic pain in women with special consideration to endometriosis. F1000Res. 2020;9: F1000 Faculty Rev-83. https://doi.org/10.12688/f1000research.20750.1. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244–56. https://doi.org/10.1056/NEJMra1810764. Kuznetsov L, Dworzynski K, Davies M, Overton C; on behalf of the Guideline Committee. Diagnosis and management of endometriosis: summary of NICE guidance. BMJ. 2017;358:j3935. https://doi.org/10.1136/bmj.j3935 Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al; World Endometriosis Research Foundation Global Study of Women's Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366–373.e8. https://doi.org/10.1016/j.fertnstert.2011.05.090 Maddern J, Grundy L, Castro J, Brierley SM. Pain in endometriosis. Front Cell Neurosci. 2020;6(14):590823. https://doi.org/10.3389/fncel.2020.590823. Howard FM. Endometriosis and mechanisms of pelvic pain. J Minim Invasive Gynecol. 2009;16(5):540–50. https://doi.org/10.1016/j.jmig.2009.06.017. Morotti M, Vincent K, Brawn J, Zondervan KT, Becker CM. Peripheral changes in endometriosis-associated pain. Hum Reprod Update. 2014;20(5):717–36. https://doi.org/10.1093/humupd/dmu021. Carey ET, Till SR, As-Sanie S. Pharmacological management of chronic pelvic pain in women. Drugs. 2017;77(3):285–301. https://doi.org/10.1007/s40265-016-0687-8. Allaire C, Williams C, Bodmer-Roy S, Zhu S, Arion K, Ambacher K, et al. Chronic pelvic pain in an interdisciplinary setting: 1-year prospective cohort. Am J Obstet Gynecol. 2018;218(1):114.e1-114.e12. https://doi.org/10.1016/j.ajog.2017.10.002. Orr NL, Wahl KJ, Lisonek M, Joannou A, Noga H, Albert A, Bedaiwy MA, Williams C, Allaire C, Yong PJ. Central sensitization inventory in endometriosis. Pain. 2022;163(2):e234–45. https://doi.org/10.1097/j.pain.0000000000002351. Elbasueny B, Geerts M, Yang EC, Allaire C, Yong PJ, Bedaiwy MA. Medical treatments of endometriosis: a review. Reproductive and Developmental Medicine. 2023;7(3):166–79. https://doi.org/10.1097/RD9.0000000000000053. Bedaiwy MA, Allaire C, Yong P, Alfaraj S. Medical management of endometriosis in patients with chronic pelvic pain. Semin Reprod Med. 2017;35(1):38–53. https://doi.org/10.1055/s-0036-1597308. Becker CM, Gattrell WT, Gude K, Singh SS. Reevaluating response and failure of medical treatment of endometriosis: a systematic review. Fertil Steril. 2017;108(1):125–36. https://doi.org/10.1016/j.fertnstert.2017.05.004. Vincent K, Kennedy S, Stratton P. Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the Art and Science of Endometriosis meeting. Fertil Steril. 2010;93(1):62–7. https://doi.org/10.1016/j.fertnstert.2008.09.056 Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–13. https://doi.org/10.1046/j.1525-1497.2001.016009606.x. Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7. https://doi.org/10.1001/archinte.166.10.1092. Osman A, Barrios FX, Kopper BA, Hauptmann W, Jones J, O’Neill E. Factor structure, reliability, and validity of the pain catastrophizing scale. J Behav Med. 1997;20(6):589–605. https://doi.org/10.1023/a:1025570508954. Jones G, Kennedy S, Barnard A, Wong J, Jenkinson C. Development of an endometriosis quality-of-life instrument: the Endometriosis health profile-30. Obstet Gynecol. 2001;98(2):258–64. https://doi.org/10.1016/s0029-7844(01)01433-8. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130(5):1377–90. https://doi.org/10.1053/j.gastro.2006.03.008. Meijlink JM. Interstitial cystitis and the painful bladder: a brief history of nomenclature, definitions and criteria. Int J Urol. 2014;21(Suppl 1):4–12. https://doi.org/10.1111/iju.12307. Yong PJ, Mui J, Allaire C, Williams C. Pelvic floor tenderness in the etiology of superficial dyspareunia. J Obstet Gynaecol Can. 2014;36(11):1002–9. https://doi.org/10.1016/S1701-2163(15)30414-X. Yosef A, Allaire C, Williams C, Ahmed AG, Al-Hussaini T, Abdellah MS, et al. Multifactorial contributors to the severity of chronic pelvic pain in women. Am J Obstet Gynecol. 2016;215(6):760.e1-760.e14. https://doi.org/10.1016/j.ajog.2016.07.023. Jarrell JF, Vilos GA, Allaire C, Burgess S, Fortin C, Gerwin R, et al; Chronic Pelvic Pain Working Group; Society of Obstetricians and Gynaecologists of Canada. Consensus guidelines for the management of chronic pelvic pain. J Obstet Gynaecol Can. 2005;27(9):869–910. English, French. https://doi.org/10.1016/s1701-2163(16)30993-8 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. https://doi.org/10.1002/uog.15955. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–21. https://doi.org/10.1016/s0015-0282(97)81391-x Sinaii N, Cleary SD, Younes N, Ballweg ML, Stratton P. Treatment utilization for endometriosis symptoms: a cross-sectional survey study of lifetime experience. Fertil Steril. 2007;87(6):1277–86. https://doi.org/10.1016/j.fertnstert.2006.11.051. Yong PJ, Alsowayan N, Noga H, Williams C, Allaire C, Lisonkova S, et al. CHC for pelvic pain in women with endometriosis: ineffectiveness or discontinuation due to side-effects. Hum Reprod Open. 2020;2020(2):hoz040. https://doi.org/10.1093/hropen/hoz040 Nirgianakis K, Vaineau C, Agliati L, McKinnon B, Gasparri ML, Mueller MD. Risk factors for non-response and discontinuation of Dienogest in endometriosis patients: a cohort study. Acta Obstet Gynecol Scand. 2021;100(1):30–40. https://doi.org/10.1111/aogs.13969. Singh S, Soliman AM, Rahal Y, Robert C, Defoy I, Nisbet P, Leyland N. Prevalence, symptomatic burden, and diagnosis of endometriosis in Canada: cross-sectional survey of 30 000 women. J Obstet Gynaecol Can. 2020;42(7):829–38. https://doi.org/10.1016/j.jogc.2019.10.038. Bernuit D, Ebert AD, Halis G, Strothmann A, Gerlinger C, Geppert K, et al. Female perspectives on endometriosis: findings from the uterine bleeding and pain women’s research study. J Endometr. 2011;3(2):73–85. https://doi.org/10.5301/JE.2011.8525. Levy AR, Osenenko KM, Lozano-Ortega G, Sambrook R, Jeddi M, Bélisle S, et al. Economic burden of surgically confirmed endometriosis in Canada. J Obstet Gynaecol Can. 2011;33(8):830–7. https://doi.org/10.1016/S1701-2163(16)34986-6. Surrey ES, Soliman AM, Johnson SJ, Davis M, Castelli-Haley J, Snabes MC. Risk of developing comorbidities among women with endometriosis: a retrospective matched cohort study. J Womens Health (Larchmt). 2018;27(9):1114–23. https://doi.org/10.1089/jwh.2017.6432. As-Sanie S, Harris RE, Harte SE, Tu FF, Neshewat G, Clauw DJ. Increased pressure pain sensitivity in women with chronic pelvic pain. Obstet Gynecol. 2013;122(5):1047–55. https://doi.org/10.1097/AOG.0b013e3182a7e1f5. Giamberardino MA, Costantini R, Affaitati G, Fabrizio A, Lapenna D, Tafuri E, et al. Viscero-visceral hyperalgesia: characterization in different clinical models. Pain. 2010;151(2):307–22. https://doi.org/10.1016/j.pain.2010.06.023. Dell JR, Mokrzycki ML, Jayne CJ. Differentiating interstitial cystitis from similar conditions commonly seen in gynecologic practice. Eur J Obstet Gynecol Reprod Biol. 2009;144(2):105–9. https://doi.org/10.1016/j.ejogrb.2009.02.050. Mease PJ, Clauw DJ, Arnold LM, Goldenberg DL, Witter J, Williams DA, et al. Fibromyalgia syndrome. J Rheumatol. 2005;32(11):2270–7. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–15. https://doi.org/10.1016/j.pain.2010.09.030. Aredo JV, Heyrana KJ, Karp BI, Shah JP, Stratton P. Relating chronic pelvic pain and endometriosis to signs of sensitization and myofascial pain and dysfunction. Semin Reprod Med. 2017;35(1):88–97. https://doi.org/10.1055/s-0036-1597123. Jarrell J. Myofascial dysfunction in the pelvis. Curr Pain Headache Rep. 2004;8(6):452–6. https://doi.org/10.1007/s11916-004-0066-0. 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. https://doi.org/10.1016/j.fertnstert.2009.01.071. Tracey I. Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat Med. 2010;16(11):1277–83. https://doi.org/10.1038/nm.2229. Vannuccini S, Lazzeri L, Orlandini C, Morgante G, Bifulco G, Fagiolini A, et al. Mental health, pain symptoms and systemic comorbidities in women with endometriosis: a cross-sectional study. J Psychosom Obstet Gynaecol. 2018;39(4):315–20. https://doi.org/10.1080/0167482X.2017.1386171. Facchin F, Barbara G, Saita E, Mosconi P, Roberto A, Fedele L, et al. Impact of endometriosis on quality of life and mental health: pelvic pain makes the difference. J Psychosom Obstet Gynaecol. 2015;36(4):135–41. https://doi.org/10.3109/0167482X.2015.1074173. Tucker DR, Noga HL, Lee C, Chiu DS, Bedaiwy MA, Williams C, et al. Pelvic pain comorbidities associated with quality of life after endometriosis surgery. Am J Obstet Gynecol. 2023;229(2):147.e1-147.e20. https://doi.org/10.1016/j.ajog.2023.04.040. Martin CE, Johnson E, Wechter ME, Leserman J, Zolnoun DA. Catastrophizing: a predictor of persistent pain among women with endometriosis at 1 year. Hum Reprod. 2011;26(11):3078–84. https://doi.org/10.1093/humrep/der292. Carey ET, Martin CE, Siedhoff MT, Bair ED, As-Sanie S. Biopsychosocial correlates of persistent postsurgical pain in women with endometriosis. Int J Gynaecol Obstet. 2014;124(2):169–73. https://doi.org/10.1016/j.ijgo.2013.07.033. Weijenborg PT, Ter Kuile MM, Gopie JP, Spinhoven P. Predictors of outcome in a cohort of women with chronic pelvic pain - a follow-up study. Eur J Pain. 2009;13(7):769–75. https://doi.org/10.1016/j.ejpain.2008.09.002. Gerlinger C, Schumacher U, Wentzeck R, Uhl-Hochgräber K, Solomayer EF, Schmitz H, et al. How can we measure endometriosis-associated pelvic pain? Journal of Endometriosis. 2012;4(3):109–16. https://doi.org/10.5301/JE.2012.97. De Graaff AA, D'Hooghe TM, Dunselman GA, Dirksen CD, Hummelshoj L; WERF EndoCost Consortium; Simoens S. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013 Oct;28(10):2677–85. https://doi.org/10.1093/humrep/det284 Warzecha D, Szymusik I, Wielgos M, Pietrzak B. The impact of Endometriosis on the quality of life and the incidence of depression-a cohort study. Int J Environ Res Public Health. 2020;17(10): 3641. https://doi.org/10.3390/ijerph17103641. Reis FM, Coutinho LM, Vannuccini S, Luisi S, Petraglia F. Is stress a cause or a consequence of endometriosis? Reprod Sci. 2020;27(1):39–45. https://doi.org/10.1007/s43032-019-00053-0. Lazzeri L, Di Giovanni A, Exacoustos C, Tosti C, Pinzauti S, Malzoni M, et al. Preoperative and postoperative clinical and transvaginal ultrasound findings of adenomyosis in patients with deep infiltrating endometriosis. Reproductive Sciences (Thousand Oaks, Calif). 2014;21(8):1027–33. https://doi.org/10.1177/1933719114522520. Peric H, Fraser IS. The symptomatology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):547–55. https://doi.org/10.1016/j.bpobgyn.2006.01.006. Bourdon M, Santulli P, Marcellin L, Maignien C, Maitrot-Mantelet L, Bordonne C, et al. Adenomyosis: An update regarding its diagnosis and clinical features. J Gynecol Obstet Hum Reprod. 2021;50(10): 102228. https://doi.org/10.1016/j.jogoh.2021.102228. Dason ES, Maxim M, Sanders A, Papillon-Smith J, Ng D, Chan C, et al. Guideline No. 437: diagnosis and management of adenomyosis. J Obstet Gynaecol Can. 2023;45(6):417–429.e1. https://doi.org/10.1016/j.jogc.2023.04.008 Elbasueny B, Geerts M, Allaire C, Yong PJ, Bedaiwy MA. Medical treatment of adenomyosis. Curr Obstet Gynecol Rep. 2022;11(2):103–17. https://doi.org/10.1007/s13669-022-00325-8. Clark TJ, Stevenson H. Endometrial polyps and abnormal uterine bleeding (AUB-P): what is the relationship, how are they diagnosed and how are they treated? Best Pract Res Clin Obstet Gynaecol. 2017;40:89–104. https://doi.org/10.1016/j.bpobgyn.2016.09.005. Harada T, Kosaka S, Elliesen J, Yasuda M, Ito M, Momoeda M. Ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen for the management of endometriosis-associated pelvic pain: a randomized controlled trial. Fertil Steril. 2017;108(5):798–805. https://doi.org/10.1016/j.fertnstert.2017.07.1165. Vercellini P, Buggio L, Berlanda N, Barbara G, Somigliana E, Bosari S. Estrogen-progestins and progestins for the management of endometriosis. Fertil Steril. 2016;106(7):1552-1571.e2. https://doi.org/10.1016/j.fertnstert.2016.10.022. Capezzuoli T, Rossi M, La Torre F, Vannuccini S, Petraglia F. Hormonal drugs for the treatment of endometriosis. Curr Opin Pharmacol. 2022;67: 102311. https://doi.org/10.1016/j.coph.2022.102311. Arnold LM, Goldenberg DL, Stanford SB, Lalonde JK, Sandhu HS, Keck PE Jr., et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56(4):1336–44. https://doi.org/10.1002/art.22457. Horne AW, Vincent K, Hewitt CA, Middleton LJ, Koscielniak M, Szubert W, GaPP2 collaborative, et al. Gabapentin for chronic pelvic pain in women (GaPP2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2020;396(10255):909–17. https://doi.org/10.1016/S0140-6736(20)31693-7. Sator-Katzenschlager SM, Scharbert G, Kress HG, Frickey N, Ellend A, Gleiss A, et al. Chronic pelvic pain treated with gabapentin and amitriptyline: a randomized controlled pilot study. Wien Klin Wochenschr. 2005;117(21–22):761–8. https://doi.org/10.1007/s00508-005-0464-2. Funding This study was supported by the Canadian Society for the Advancement of Gynecologic Excellence (CanSAGE)/Pfizer early career investigator grant and grants from the Canadian Institutes of Health Research (CIHR): MOP-142273 and PJT-156084. The first author (B.F) is funded by a scholarship from the Egyptian Ministry of Higher Education. Author information Authors and Affiliations Contributions All authors met the criteria for authorship. C.W., C.L., C.A., P.J.Y., and M.A.B. managed the patients in the Centre for Pelvic Pain and Endometriosis at BC Women’s Hospital and Health Centre. B.F., R.H., and P.J.Y. granted the funding for the study. B.F., P.J.Y., and M.A.B. designed the study, wrote the study protocol, and obtained the ethics approval. Y.D.L. analyzed the data. B.F., Y.D.L., P.J.Y., and M.A.B. and interpreted the results. B.F. prepared first draft of the manuscript. B.F., M.E.A., N.K.A., A.E., Y.D.L., and R.H. edited the manuscript. C.W., C.L., C.A., P.J.Y., and M.A.B. critically revised the article and finalized the manuscript. All authors approved the final version of the article and were accountable for all aspects of the work. Corresponding author Ethics declarations Ethics Approval This study was approved by the University of British Columbia and BC Women’s Hospital Ethics Committee on January 25, 2022. Approval number (H22-00036). Consent to Participate Informed consent was obtained from all participants included in the study. Consent for Publication Not applicable. Prior Presentation Part of this work has been presented orally by the corresponding author at the 15th World Congress Endometriosis in Edinburgh, Scotland. May 3rd—6th, 2023. Clinical Trial Registration N/A Competing interests - C.A: Advisory board for AbbVie and Pfizer. -P.J.Y: Research grants from Canadian Institutes of Health Research (CIHR) and a. Michael Smith Foundation for Health Research Grant. - M.A.B: Research grants from Canadian Institutes of Health Research (CIHR) and Ferring Pharmaceutical. He is on the advisory board for AbbVie, Pfizer, and Baxter. - Other authors do not have any declarations of interest. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Fayek, B., Liu, Y.D., Williams, C. et al. Factors Affecting Hormonal Therapy Ineffectiveness and Discontinuation due to Adverse Effects in Patients with Endometriosis-Associated Pain. Reprod. Sci. 32, 2946–2963 (2025). https://doi.org/10.1007/s43032-025-01947-y Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-025-01947-y