Evaluation of Endpoints Used in Clinical Trials on Adenomyosis - A Systematic Review

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Abstract

Adenomyosis lacks approved pharmacological treatment even after decades of its identification. We performed this study to review the status of clinical research on adenomyosis for finding an effective drug therapy and to identify the most common endpoints used in adenomyosis trials. A systematic search was performed in the PubMed and Clinicaltrials.gov registries to identify interventional trials for analysis without any time and language restrictions. Our search revealed that barely 15 drugs have been assessed for the management of adenomyosis from 2001 to 2021. Among these, LNG-IUS was found to be the most evaluated drug, followed by dienogest. In these trials, the most commonly assessed endpoints included VAS, NPRS for pain, haemoglobin and PBAC for menstrual bleeding, uterine volume, and serum estradiol. There appears to be a need for developing a comprehensive score that takes into consideration all disease symptoms as well as incorporates some objective elements to evaluate the disease.

Graphical Abstract

[1]
Antero MF, Ayhan A, Segars J, Shih IM. Pathology and pathogenesis of adenomyosis. Semin Reprod Med 2020; 38(2-03): 108-8.
[http://dx.doi.org/10.1055/s-0040-1718922]
[2]
Parazzini F, Mais V, Cipriani S, Busacca M, Venturini P. Determinants of adenomyosis in women who underwent hysterectomy for benign gynecological conditions: Results from a prospective multicentric study in Italy. Eur J Obstet Gynecol Reprod Biol 2009; 143(2): 103-6.
[http://dx.doi.org/10.1016/j.ejogrb.2008.12.010] [PMID: 19232812]
[3]
Di Donato N, Montanari G, Benfenati A, et al. Prevalence of adenomyosis in women undergoing surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol 2014; 181: 289-93.
[http://dx.doi.org/10.1016/j.ejogrb.2014.08.016] [PMID: 25201608]
[4]
Dessouky R, Gamil SA, Nada MG, Mousa R, Libda Y. Management of uterine adenomyosis: current trends and uterine artery embolization as a potential alternative to hysterectomy. Insights Imaging 2019; 10(1): 48.
[http://dx.doi.org/10.1186/s13244-019-0732-8] [PMID: 31030317]
[5]
Oliveira MAP, Crispi CP Jr, Brollo LC, Crispi CP, De Wilde RL. Surgery in adenomyosis. Arch Gynecol Obstet 2018; 297(3): 581-9.
[http://dx.doi.org/10.1007/s00404-017-4603-6] [PMID: 29197987]
[6]
Vannuccini S, Petraglia F. Recent advances in understanding and managing adenomyosis [version 1; peer review: 2 approved]. F1000Research 2019; 8(F1000 Faculty Rev): 283.
[http://dx.doi.org/10.12688/f1000research.17242.1]
[7]
Abdel-Fattah H, El-Lakkany N, Helal AS, Mosbah A, Abdel-Hady E-S, Abdel-Shaheed M. Conservative laparoscopic electrocoagulation adenomyolysis for the management of symptomatic adenomyosis. Gynecol Surg 2015; 12(3): 139-47.
[http://dx.doi.org/10.1007/s10397-015-0890-8]
[8]
Klimek L, Bergmann KC, Biedermann T, et al. Visual analogue scales (VAS): Measuring instruments for the documentation of symptoms and therapy monitoring in cases of allergic rhinitis in everyday health care. Allergo J Int 2017; 26(1): 16-24.
[http://dx.doi.org/10.1007/s40629-016-0006-7] [PMID: 28217433]
[9]
Flynn D, van Schaik P, van Wersch A. A comparison of multi-item likert and visual analogue scales for the assessment of transactionally defined coping. Eur J Psychol Assess 2004; 20(1): 49-58.
[http://dx.doi.org/10.1027/1015-5759.20.1.49]
[10]
Brazier J, Ratcliffe J. Measurement and Valuation of Health for Economic Evaluation, International Encyclopedia of Public Health. (2nd ed.). Academic Press 2017; pp. 586-93.
[http://dx.doi.org/10.1016/B978-0-12-803678-5.00457-4]
[11]
Murphy DF, McDonald A, Power C, Unwin A, MacSullivan R. Measurement of Pain. Clin J Pain 1987; 3(4): 197-200.
[http://dx.doi.org/10.1097/00002508-198712000-00003]
[12]
Gerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz H, Seitz C. Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: Analyses of two placebo-controlled, randomized trials. Health Qual Life Outcomes 2010; 8(1): 138.
[http://dx.doi.org/10.1186/1477-7525-8-138]
[13]
Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med 1969; 62(10): 989-93.
[http://dx.doi.org/10.1177/003591576906201005] [PMID: 4899510]
[14]
Domenica A, Lambert BS, Boutris N, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev 2018; 2(3): e088.
[http://dx.doi.org/10.5435/JAAOSGlobal-D-17-00088]
[15]
Alfonsin MM, Chapon R, de Souza CAB, Genro VK, Mattia MMC, Cunha-Filho JS. Correlations among algometry, the visual analogue scale, and the numeric rating scale to assess chronic pelvic pain in women. Eur J Obstet Gynecol Reprod Biol X 2019; 3: 100037.
[http://dx.doi.org/10.1016/j.eurox.2019.100037] [PMID: 31403125]
[16]
Brucker SY, Huebner M, Wallwiener M, et al. Clinical characteristics indicating adenomyosis coexisting with leiomyomas: A retrospective, questionnaire-based study. Fertil Steril 2014; 101(1): 237-241.e1.
[http://dx.doi.org/10.1016/j.fertnstert.2013.09.038] [PMID: 24188881]
[17]
Magnay JL, O’Brien S, Gerlinger C, Seitz C. Pictorial methods to assess heavy menstrual bleeding in research and clinical practice: A systematic literature review. BMC Womens Health 2020; 20(1): 24.
[http://dx.doi.org/10.1186/s12905-020-0887-y] [PMID: 32041594]
[18]
El-Nashar SA, Shazly SAM, Famuyide AO. Pictorial blood loss assessment chart for quantification of menstrual blood loss: A systematic review. Gynecol Surg 2015; 12(3): 157-63.
[http://dx.doi.org/10.1007/s10397-015-0893-5]
[19]
Magnay JL, O’Brien S, Gerlinger C, Seitz C. A systematic review of methods to measure menstrual blood loss. BMC Womens Health 2018; 18(1): 142.
[http://dx.doi.org/10.1186/s12905-018-0627-8] [PMID: 30134884]
[20]
van Eijkeren MA, Scholten PC, Christiaens GCML, Alsbach GPJ, Haspels AA. The alkaline hematin method for measuring menstrual blood loss-a modification and its clinical use in menorrhagia. Eur J Obstet Gynecol Reprod Biol 1986; 22(5-6): 345-51.
[http://dx.doi.org/10.1016/0028-2243(86)90124-3] [PMID: 3770285]
[21]
Magnay JL, Schönicke G, Nevatte TM, O’Brien S, Junge W. Validation of a rapid alkaline hematin technique to measure menstrual blood loss on feminine towels containing superabsorbent polymers. Fertil Steril 2011; 96(2): 394-8.
[http://dx.doi.org/10.1016/j.fertnstert.2011.05.096] [PMID: 21719001]
[22]
Zakherah MS, Sayed GH, El-Nashar SA, Shaaban MM. Pictorial blood loss assessment chart in the evaluation of heavy menstrual bleeding: Diagnostic accuracy compared to alkaline hematin. Gynecol Obstet Invest 2011; 71(4): 281-4.
[http://dx.doi.org/10.1159/000320336] [PMID: 21228538]
[23]
Warner PE, Critchley HOD, Lumsden MA, Campbell-Brown M, Douglas A, Murray GD. Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol 2004; 190(5): 1216-23.
[http://dx.doi.org/10.1016/j.ajog.2003.11.015] [PMID: 15167821]
[24]
Van-den Bosch T, de Bruijn AM, de Leeuw RA, et al. A sonographic classification and reporting system for diagnosing adenomyosis. Ultrasound Obstet Gynecol 2019; 53(3): 576-82.
[http://dx.doi.org/10.1002/uog.19096] [PMID: 29790217]
[25]
Kishi Y, Suginami H, Kuramori R, Yabuta M, Suginami R, Taniguchi F. Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification. Am J Obstet Gynecol 2012; 207(2): 114.e1-7.
[http://dx.doi.org/10.1016/j.ajog.2012.06.027] [PMID: 22840719]
[26]
Kung FT, Chang SY. The relationship between ultrasonic volume and actual weight of pathologic uterus. Gynecol Obstet Invest 1996; 42(1): 35-8.
[http://dx.doi.org/10.1159/000291886] [PMID: 8840176]
[27]
Goldstein SR, Horii SC, Snyder JR, Raghavendra BN, Subramanyam B. Estimation of nongravid uterine volume based on a nomogram of gravid uterine volume: Its value in gynecologic uterine abnormalities. Obstet Gynecol 1988; 72(1): 86-90.
[PMID: 3288932]
[28]
Tamai K, Togashi K, Ito T, Morisawa N, Fujiwara T, Koyama T. MR imaging findings of adenomyosis: Correlation with histopathologic features and diagnostic pitfalls. Radiographics 2005; 25(1): 21-40.
[http://dx.doi.org/10.1148/rg.251045060] [PMID: 15653584]
[29]
Exacoustos C, Brienza L, Di Giovanni A, et al. Adenomyosis: Three‐dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet Gynecol 2011; 37(4): 471-9.
[http://dx.doi.org/10.1002/uog.8900] [PMID: 21433167]
[30]
Agostinho L, Cruz R, Osório F, Alves J, Setúbal A, Guerra A. MRI for adenomyosis: A pictorial review. Insights Imaging 2017; 8(6): 549-56.
[http://dx.doi.org/10.1007/s13244-017-0576-z] [PMID: 28980163]
[31]
Kocaoz Semra, Cirpan R, Degirmencioglu AZ. The prevalence and impacts heavy menstrual bleeding on anemia, fatigue and quality of life in women of reproductive age. Pak J Med Sci 2019; 35(2): 365-70.
[http://dx.doi.org/10.12669/pjms.35.2.644]
[32]
Peuranpää P, Heliövaara-Peippo S, Fraser I, Paavonen J, Hurskainen R. Effects of anemia and iron deficiency on quality of life in women with heavy menstrual bleeding. Acta Obstet Gynecol Scand 2014; 93(7): 654-60.
[http://dx.doi.org/10.1111/aogs.12394] [PMID: 24912842]
[33]
Whitehead RD Jr, Zhang M, Sternberg MR, et al. Effects of preanalytical factors on hemoglobin measurement: A comparison of two HemoCue® point-of-care analyzers. Clin Biochem 2017; 50(9): 513-20.
[http://dx.doi.org/10.1016/j.clinbiochem.2017.04.006] [PMID: 28412284]
[34]
Whitehead RD Jr, Mei Z, Mapango C, Jefferds MED. Methods and analyzers for hemoglobin measurement in clinical laboratories and field settings. Ann N Y Acad Sci 2019; 1450(1): 147-71.
[http://dx.doi.org/10.1111/nyas.14124] [PMID: 31162693]
[35]
Yada TA, Dessie Y, Darghawth R, Wilfong T, Kure MA, Roba KT. Magnitude of intestinal parasitosis, malnutrition, and predictors of anemia among nonpregnant reproductive-age women attending healthcare services in olenchity general hospital, central ethiopia. Frontiers in Tropical Diseases 2021; 2: 655690.
[http://dx.doi.org/10.3389/fitd.2021.655690]
[36]
Nelson AL, Ritchie JJ. Severe anemia from heavy menstrual bleeding requires heightened attention. Am J Obstet Gynecol 2015; 213(1): 97.e1-6.
[http://dx.doi.org/10.1016/j.ajog.2015.04.023] [PMID: 25935784]
[37]
Api O, Breyman C, Çetiner M, Demir C, Ecder T. Diagnosis and treatment of iron deficiency anemia during pregnancy and the postpartum period: Iron deficiency anemia working group consensus report. Turk J Obstet Gynecol 2015; 12(3): 173-81.
[http://dx.doi.org/10.4274/tjod.01700]
[38]
Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol Med 2013; 19(3): 197-209.
[http://dx.doi.org/10.1016/j.molmed.2012.12.007]
[39]
Garavaglia E, Audrey S, Annalisa I, et al. Adenomyosis and its impact on women fertility. Iran J Reprod Med 2015; 13(6): 327-36.
[PMID: 26330846]
[40]
Brosens I, Derwig I, Brosens J, Fusi L, Benagiano G, Pijnenborg R. The enigmatic uterine junctional zone: The missing link between reproductive disorders and major obstetrical disorders? Hum Reprod 2010; 25(3): 569-74.
[http://dx.doi.org/10.1093/humrep/dep474] [PMID: 20085913]
[41]
Huhtinen K, Desai R, Ståhle M, et al. Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J Clin Endocrinol Metab 2012; 97(11): 4228-35.
[http://dx.doi.org/10.1210/jc.2012-1154]
[42]
Leyendecker G, Kunz G, Kissler S, Wildt L. Adenomyosis and reproduction. Best Pract Res Clin Obstet Gynaecol 2006; 20(4): 523-46.
[http://dx.doi.org/10.1016/j.bpobgyn.2006.01.008] [PMID: 16520094]
[43]
Chen YJ, Li HY, Huang CH, et al. Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol 2010; 222(3): 261-70.
[http://dx.doi.org/10.1002/path.2761] [PMID: 20814901]
[44]
Kouides PA. Bleeding symptom assessment and hemostasis evaluation of menorrhagia. Curr Opin Hematol 2008; 15(5): 465-72.
[http://dx.doi.org/10.1097/MOH.0b013e32830a4ed4] [PMID: 18695369]
[45]
Hapangama DK, Bulmer JN. Pathophysiology of heavy menstrual bleeding. Womens Health (Lond Engl) 2016; 12(1): 3-13.
[http://dx.doi.org/10.2217/whe.15.81] [PMID: 26695831]
[46]
Alghadir AH, Anwer S, Iqbal A, Iqbal ZA. Test-retest reliability, validity, and minimum detectable change of visual analog, numerical rating, and verbal rating scales for measurement of osteoarthritic knee pain. J Pain Res 2018; 11: 851-6.
[http://dx.doi.org/10.2147/JPR.S158847]
[47]
Haefeli M, Elfering A. Pain assessment. Eur Spine J 2006; 15 (Suppl. 1): S17-24.
[http://dx.doi.org/10.1007/s00586-005-1044-x]
[48]
Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole MR. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94(2): 149-58.
[http://dx.doi.org/10.1016/S0304-3959(01)00349-9] [PMID: 11690728]
[49]
Pathak A, Sharma S, Jensen MP. The utility and validity of pain intensity rating scales for use in developing countries. Pain Rep 2018; 3(5): e672.
[http://dx.doi.org/10.1097/PR9.0000000000000672] [PMID: 30534623]
[50]
Bland JM, Altman DG. A note on the use of the intraclass correlation coefficient in the evaluation of agreement between two methods of measurement. Comput Biol Med 1990; 20(5): 337-40.
[http://dx.doi.org/10.1016/0010-4825(90)90013-F] [PMID: 2257734]
[51]
Sharma S, Palanchoke J, Reed D, Haxby Abbott J. Translation, cross-cultural adaptation and psychometric properties of the Nepali versions of numerical pain rating scale and global rating of change. Health Qual Life Outcomes 2017; 15(1): 236.
[http://dx.doi.org/10.1186/s12955-017-0812-8] [PMID: 29202878]
[52]
Osuga Y, Hayashi K, Kanda S. Long‐term use of dienogest for the treatment of primary and secondary dysmenorrhea. J Obstet Gynaecol Res 2020; 46(4): 606-17.
[http://dx.doi.org/10.1111/jog.14209] [PMID: 32050307]
[53]
Li Q, Ding Y, Zhang XY, Feng WW, Hua KQ. Drug therapy for adenomyosis: a prospective, nonrandomized, parallel-controlled study. J Int Med Res 2018; 46(5): 1855-65.
[http://dx.doi.org/10.1177/0300060517752997] [PMID: 29552942]
[54]
Osuga Y, Fujimoto-Okabe H, Hagino A. Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double-blind, multicenter, placebo-controlled study. Fertil Steril 2017; 108(4): 673-8.
[http://dx.doi.org/10.1016/j.fertnstert.2017.07.021] [PMID: 28911934]
[55]
Tan AL, Luo RY, Gong M. Value of using gonadotropin-releasing hormone agonist pretreatment in adenomyosis patients before adenomyomectomy. Zhonghua Fu Chan Ke Za Zhi 2016; 51(12): 909-13.
[http://dx.doi.org/10.3760/cma.j.issn.0529-567X.2016.12.006] [PMID: 28057126]
[56]
Shaaban OM, Ali MK, Sabra AMA, Abd El Aal DEM. Levonorgestrel-releasing intrauterine system versus a low-dose combined oral contraceptive for treatment of adenomyotic uteri: A randomized clinical trial. Contraception 2015; 92(4): 301-7.
[http://dx.doi.org/10.1016/j.contraception.2015.05.015] [PMID: 26071673]
[57]
Wang Y, Jiang X, Wang S. The influence of mifepristone to caspase 3 expression in adenomyosis. Clin Exp Obstet Gynecol 2014; 41(2): 154-7.
[http://dx.doi.org/10.12891/ceog15872014] [PMID: 24779241]
[58]
Ekin M, Cengiz H, Ayağ ME, Kaya C, Yasar L, Savan K. Effects of the levonorgestrel-releasing intrauterine system on urinary symptoms in patients with adenomyosis. Eur J Obstet Gynecol Reprod Biol 2013; 170(2): 517-20.
[http://dx.doi.org/10.1016/j.ejogrb.2013.07.019] [PMID: 23916583]
[59]
Zhang P, Song K, Li L, Yukuwa K, Kong B. Efficacy of combined levonorgestrel-releasing intrauterine system with gonadotropin-releasing hormone analog for the treatment of adenomyosis. Med Princ Pract 2013; 22(5): 480-3.
[http://dx.doi.org/10.1159/000351431] [PMID: 23796720]
[60]
Badawy AM, Elnashar AM, Mosbah AA. Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial. AOGS 2012; 91(4): 489-95.
[http://dx.doi.org/10.1111/j.1600-0412.2012.01350.x]
[61]
Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril 2011; 95(2): 497-502.
[http://dx.doi.org/10.1016/j.fertnstert.2010.10.009] [PMID: 21074150]
[62]
Sheng J, Zhang WY, Zhang JP, Lu D. The LNG-IUS study on adenomyosis: A 3-year follow-up study on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrhea associated with adenomyosis. Contraception 2009; 79(3): 189-93.
[http://dx.doi.org/10.1016/j.contraception.2008.11.004] [PMID: 19185671]
[63]
Cho S, Nam A, Kim H, et al. Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am J Obstet Gynecol 2008; 198(4): 373.e1-7.
[http://dx.doi.org/10.1016/j.ajog.2007.10.798] [PMID: 18177833]
[64]
Liu X, Guo SW. A pilot study on the off-label use of valproic acid to treat adenomyosis. Fertil Steril 2008; 89(1): 246-50.
[http://dx.doi.org/10.1016/j.fertnstert.2006.11.009] [PMID: 17239872]
[65]
Ming he, Zhang YD. Clinical study of levonorgestrel-releasing intrauterine system for adenomyosis. Nan Fang Yi Ke Da Xue Xue Bao 2006; 26(12): 1794-6.
[66]
Laoag-Fernandez JB, Maruo T, Pakarinen P, Spitz IM, Johansson E. Effects of levonorgestrel-releasing intra-uterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium in adenomyosis. Hum Reprod 2003; 18(4): 694-9.
[http://dx.doi.org/10.1093/humrep/deg179] [PMID: 12660258]
[67]
Low Molecular Weight Heparin on the Adenomyosis Patients'IVF-ET Outcome. Available from: https://clinicaltrials.gov/ct2/show/NCT04741295 [Accessed on 29th October 2021].
[68]
Aspirin in the Treatment of Pregnant Women With Adenomyosis on Reducing Preterm Delivery. Available from: https://clinicaltrials.gov/ct2/show/NCT04535804 [Accessed on 29th October 2021].
[69]
Modified Downregulation for Women With Adenomyosis of the Uterus Prior to Frozen-thawed Embryo Transfer (MODA). Available from: https://clinicaltrials.gov/ct2/show/NCT03946722 [Accessed on 29th October 2021].
[70]
Impact of Ultra-long Versus Long Down-regulation Protocol on IVF/ICSI in Adenomyosis (ADENOFIV). Available from: https://clinicaltrials.gov/ct2/show/NCT03940807 [Accessed on 29th October 2021].
[71]
Dienogest for Treatment of Adenomyotic Uteri. Available from: https://clinicaltrials.gov/ct2/show/NCT03890042 [Accessed on 29th October 2021].
[72]
Evaluation of Therapeutic Effect and Safety of Mifepristone in the Treatment of Adenomyosis (ETESRTA). Available from: https://clinicaltrials.gov/ct2/show/NCT03520439 [Accessed on 29th October 2021].
[73]
Role of Dienogest in the Treatment of Patient With Symptomatic Adenomyosis. Available from: https://clinicaltrials.gov/ct2/show/NCT03654144 [Accessed on 29th October 2021].
[74]
Adenomyosis: Genomic Mechanisms and Biological Response. Available from: https://clinicaltrials.gov/ct2/show/NCT03428854 [Accessed on 29th October 2021].
[75]
Levonorgestrel-releasing intrauterine system versus a low-dose combined oral contraceptive for management of adenomyosis uteri (LNG-IUDvsCOCs). Available from: https://clinicaltrials.gov/ct2/show/NCT03037944 [Accessed on 29th October 2021].
[76]
Levonorgestrel Intrauterine System and Adenomyosis. Available from: https://clinicaltrials.gov/ct2/show/NCT03104309 [Accessed on 29th October 2021].
[77]
Effect of Ulipristal Acetate on Bleeding Patterns and Dysmenorrhea in Women With Adenomyosis. Available from: https://clinicaltrials.gov/ct2/show/NCT03325868 [Accessed on 29th October 2021].
[78]
Placebo-controlled Proof of Concept Study of Epelsiban in Women With Adenomyosis. Available from: https://clinicaltrials.gov/ct2/show/NCT02794467 [Accessed on 29th October 2021].
[79]
Adenomyosis and Ulipristal Acetate (FRA-IIT-UPA). Available from: https://clinicaltrials.gov/ct2/show/NCT02587000 [Accessed on 29th October 2021].
[80]
Comparison of estrogen-progestin therapy in continuous regimen versus combination estrogen-progestin therapy in continuous regimen plus levonorgestrel-releasing intrauterine system (LNG-IUS). Available from: https://clinicaltrials.gov/ct2/show/NCT02556411 [Accessed on 29th October 2021].
[81]
Vaginal Bromocriptine for Treatment of Adenomyosis. Available from: https://clinicaltrials.gov/ct2/show/NCT01821001 [Accessed on 29th October 2021].
[82]
LNG-IUS for Treatment of Dysmenorrhea (LNGIUSAD). Available from: https://clinicaltrials.gov/ct2/show/NCT01601366 [Accessed on 29th October 2021].
[83]
Aromatase Inhibitors or GnRH-a for Uterine Adenomyosis. Available from: https://clinicaltrials.gov/ct2/show/NCT01218581 [Accessed on 29th October 2021].