Drug development for adenomyosis based on pathophysiology

Published studies are reviewed and trials on adenomyosis registered at ClinicalTrials.gov are also reviewed. Main Results A survey of the interventional trials on new drugs gave a grim picture. Among seven trials on four classes of new drugs, a single trial on aromatase inhibitors reported symptom improvement but was marred by data authenticity concerns; the only trial on oxytocin receptor (OTR) antagonist was withdrawn, two trials on dopamine receptor D2 (DRD2) agonists yielded conflicting results, and the only trial on ulipristal acetate was completed but not reported and presumed to have failed. The only drug that is reported to be efficacious is mifepristone, an old drug that induces amenorrhea in 90% of patients. On the bright side, a mouse model that apparently recapitulates one subtype of adenomyosis became available fairly recently. The big picture of the natural history of adenomyotic lesions has become clear, and the mechanisms underlying adenomyosis-induced heavy menstrual bleeding are being unveiled. Along these lines, several drugs have been tested in preclinical settings.

With a better understanding of adenomyosis pathophysiology, more druggable targets will be discovered. CONFLICT OF INTEREST STATEMENT Sun-Wei Guo is a member of the Scientific Advisory Board of Heranova, FimmCyte A.G., and E3A Healthcare, and has provided consultancy advice to these companies, as well as to Shanghai Huilun Biotechnology, but these activities had no bearing on this work.

- 1Ponsold K, Hubner M, Schade W, Oettel M, Freund R. Progestagens of the 17 alpha-CH2X-substituted 19-nortestosterone derivative type. 57. Steroids. Pharmazie. 1978; 33(12): 792–798. - 2Ponsold K. The development of a new highly potent progestagen, STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-13 beta-methylgona-4,9-dien-3-one) (proceedings). Pharmazie. 1979; 34(5–6): 312–314. - 3Kohler G, Goretzlehner G, Amon I. Therapy of endometriosis with dienogest. Zentralbl Gynakol. 1987; 109(12): 795–801. - 4Kohler G, Goretzlehner G, Brachmann K. Lipid metabolism during treatment of endometriosis with the progestin dienogest. Acta Obstet Gynecol Scand. 1989; 68(7): 633–635. - 5Pinzauti S, Lazzeri L, Tosti C, Centini G, Orlandini C, Luisi S, et al. Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms. Ultrasound Obstet Gynecol. 2015; 46(6): 730–736. - 6Chapron C, Vannuccini S, Santulli P, Abrão MS, Carmona F, Fraser IS, et al. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update. 2020; 26(3): 392–411. - 7Vannuccini S, Meleca C, Toscano F, Mertino P, Pampaloni F, Fambrini M, et al. Adenomyosis diagnosis among adolescents and young women with dysmenorrhoea and heavy menstrual bleeding. Reprod Biomed Online. 2024; 48(5):103768. - 8Kho KA, Chen JS, Halvorson LM. Diagnosis, evaluation, and treatment of adenomyosis. JAMA. 2021; 326(2): 177–178. - 9Naftalin J, Hoo W, Pateman K, Mavrelos D, Holland T, Jurkovic D. How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Hum Reprod. 2012; 27(12): 3432–3439. - 10Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health. 2012; 12: 6. - 11Farquhar C, Brosens I. Medical and surgical management of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006; 20: 603–616. - 12Harada T, Khine YM, Kaponis A, Nikellis T, Decavalas G, Taniguchi F. The impact of adenomyosis on women's fertility. Obstet Gynecol Surv. 2016; 71(9): 557–568. - 13Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod. 2014; 29(5): 964–977. - 14Gordts S, Grimbizis G, Campo R. Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis. Fertil Steril. 2018; 109(3): 380–388.e1. - 15Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006; 20(4): 449–463. - 16Guo SW. Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology. Reproduction. 2022; 164(5): R101–R121. https://doi.org/10.1530/REP-22-0224 - 17Vannuccini S, Petraglia F. Recent advances in understanding and managing adenomyosis. F1000Res. 2019; 8:F1000 Faculty Rev-283. https://doi.org/10.12688/f1000research.17242.1 - 18Osada H. Uterine adenomyosis and adenomyoma: the surgical approach. Fertil Steril. 2018; 109(3): 406–417. - 19Kishi Y, Yabuta M, Taniguchi F. Who will benefit from uterus-sparing surgery in adenomyosis-associated subfertility? Fertil Steril. 2014; 102(3): 802–807.e1. - 20Liu L, Tian H, Lin D, Zhao L, Wang H, Hao Y. Risk of recurrence and reintervention after uterine-sparing interventions for symptomatic adenomyosis: a systematic review and meta-analysis. Obstet Gynecol. 2023; 141(4): 711–723. - 21Cope AG, Ainsworth AJ, Stewart EA. Current and future medical therapies for adenomyosis. Semin Reprod Med. 2020; 38(2–03): 151–156. - 22Kitawaki J. Adenomyosis: the pathophysiology of an oestrogen-dependent disease. Best Pract Res Clin Obstet Gynaecol. 2006; 20(4): 493–502. - 23Etrusco A, Barra F, Chiantera V, Ferrero S, Bogliolo S, Evangelisti G, et al. Current medical therapy for adenomyosis: from bench to bedside. Drugs. 2023; 83(17): 1595–1611. - 24Harada T, Taniguchi F, Guo SW, Choi YM, Biberoglu KO, Tsai SJS, et al. The Asian Society of Endometriosis and Adenomyosis guidelines for managing adenomyosis. Reprod Med Biol. 2023; 22(1):e12535. - 25Donnez J, Donnez O, Brethous M, Bestel E, Garner E, Charpentier S, et al. Treatment of symptomatic uterine adenomyosis with linzagolix, an oral gonadotrophin-releasing hormone antagonist: a pilot study. Reprod Biomed Online. 2022; 44(1): 200–203. - 26Burla L, Kalaitzopoulos DR, Metzler JM, Scheiner D, Imesch P. Popularity of endocrine endometriosis drugs and limited alternatives in the present and foreseeable future: a survey among 1420 affected women. Eur J Obstet Gynecol Reprod Biol. 2021; 262: 232–238. - 27Thurnherr N, Burla L, Metzler JM, File B, Imesch P. Attitudes and perceptions of affected women towards endocrine endometriosis therapy: an international survey based on free-word association networks. Hum Reprod. 2024; 39(1): 83–92. - 28Vannuccini S, Luisi S, Tosti C, Sorbi F, Petraglia F. Role of medical therapy in the management of uterine adenomyosis. Fertil Steril. 2018; 109(3): 398–405. - 29Guo SW. Various types of adenomyosis and endometriosis: in search of optimal management. Fertil Steril. 2023; 119(5): 711–726. - 30Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992; 166(2): 740–745. https://doi.org/10.1016/0002-9378(92)91706-g - 31Brosens IA. Endometriosis—a disease because it is characterized by bleeding. Am J Obstet Gynecol. 1997; 176(2): 263–267. - 32Guo SW, Groothuis PG. Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Hum Reprod Update. 2018; 24(5): 577–598. - 33Groothuis PG, Guo SW. Drug development in endometriosis and adenomyosis: it takes more than just good science. Reprod Sci. 2018; 25(9): 1318–1329. - 34Badawy AM, Elnashar AM, Mosbah AA. Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial. Acta Obstet Gynecol Scand. 2012; 91(4): 489–495. - 35Editor's Note: Badawy, AM, Elnashar, AM, and Mosbah, AA. Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial. Acta Obstet Gynecol Scand. 2012; 91: 489–495. - 36Statement of retraction: low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol. 2022; 42(8): 3745. - 37Donnez J, Donnez O, Dolmans MM. Safety of treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. Expert Opin Drug Saf. 2016; 15(12): 1679–1686. - 38Benagiano G, Bastianelli C, Farris M, Brosens I. Selective progesterone receptor modulators: an update. Expert Opin Pharmacother. 2014; 15(10): 1403–1415. - 39Ekanem E, Talaulikar V. Medical therapy for fibroids: what next for ulipristal acetate? Adv Ther. 2021; 38(1): 137–148. - 40Gracia M, Alcala M, Ferreri J, Rius M, Ros C, Saco MA, et al. Ulipristal acetate improves clinical symptoms in women with adenomyosis and uterine myomas. J Minim Invasive Gynecol. 2018; 25(7): 1274–1280. - 41Capmas P, Brun JL, Legendre G, Koskas M, Merviel P, Fernandez H. Ulipristal acetate use in adenomyosis: a randomized controlled trial. J Gynecol Obstet Hum Reprod. 2021; 50(1):101978. - 42Conway F, Morosetti G, Camilli S, Martire FG, Sorrenti G, Piccione E, et al. Ulipristal acetate therapy increases ultrasound features of adenomyosis: a good treatment given in an erroneous diagnosis of uterine fibroids. Gynecol Endocrinol. 2019; 35(3): 207–210. - 43Calderon L, Netter A, Grob-Vaillant A, Mancini J, Siles P, Vidal V, et al. Progression of adenomyosis magnetic resonance imaging features under ulipristal acetate for symptomatic fibroids. Reprod Biomed Online. 2021; 42(3): 661–668. - 44Hong YH, Han SJ, Lee D, Kim SK, Jee BC. Adverse symptoms during short-term use of ulipristal acetate in women with uterine myomas and/or adenomyosis. J Obstet Gynaecol Res. 2019; 45(4): 865–870. - 45Middelkoop MA, Bet PM, Drenth JPH, Huirne JAF, Hehenkamp WJK. Risk-efficacy balance of ulipristal acetate compared to surgical alternatives. Br J Clin Pharmacol. 2021; 87(7): 2685–2697. - 46Fauser BC, Donnez J, Bouchard P, Barlow DH, Vazquez F, Arriagada P, et al. Safety after extended repeated use of ulipristal acetate for uterine fibroids. PLoS One. 2017; 12(3):e0173523. - 47Chodankar RR, Murray A, Nicol M, Whitaker LHR, Williams ARW, Critchley HOD. The endometrial response to modulation of ligand-progesterone receptor pathways is reversible. Fertil Steril. 2021; 116(3): 882–895. - 48Nie J, Lu Y, Liu X, Guo SW. Immunoreactivity of progesterone receptor isoform B, nuclear factor kappaB, and IkappaBalpha in adenomyosis. Fertil Steril. 2009; 92(3): 886–889. - 49Jichan N, Xishi L, Guo SW. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in adenomyosis and its rectification by a histone deacetylase inhibitor and a demethylation agent. Reprod Sci. 2010; 17(11): 995–1005. - 50Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E, Hayashi T, et al. Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations. Nat Commun. 2019; 10(1): 5785. - 51Che X, Wang J, Sun W, He J, Wang Q, Zhu D, et al. Effect of mifepristone vs placebo for treatment of adenomyosis with pain symptoms: a randomized clinical trial. JAMA Netw Open. 2023; 6(6):e2317860. - 52Andersson JK, Khan Z, Weaver AL, Vaughan LE, Gemzell-Danielsson K, Stewart EA. Vaginal bromocriptine improves pain, menstrual bleeding and quality of life in women with adenomyosis: a pilot study. Acta Obstet Gynecol Scand. 2019; 98(10): 1341–1350. - 53Guo SW, Evers JL. Lack of transparency of clinical trials on endometriosis. Obstet Gynecol. 2013; 121(6): 1281–1290. - 54Guo SW, Hummelshoj L, Olive DL, Bulun SE, D'Hooghe TM, Evers JL. A call for more transparency of registered clinical trials on endometriosis. Hum Reprod. 2009; 24(6): 1247–1254. - 55Bulun SE, Yildiz S, Adli M, Wei JJ. Adenomyosis pathogenesis: insights from next-generation sequencing. Hum Reprod Update. 2021; 27(6): 1086–1097. - 56Kobayashi H. Molecular targets for nonhormonal treatment based on a multistep process of adenomyosis development. Reprod Sci. 2023; 30(3): 743–760. - 57Huang Q, Liu X, Guo SW. Changing prostaglandin E2 (PGE(2)) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE(2) receptor EP2 and EP4. Reprod Med Biol. 2022; 21(1):e12426. - 58Huang Q, Liu X, Guo SW. Higher fibrotic content of endometriotic lesions is associated with diminished prostaglandin E2 signaling. Reprod Med Biol. 2022; 21(1):e12423. - 59Vannuccini S, Tosti C, Carmona F, Huang SJ, Chapron C, Guo SW, et al. Pathogenesis of adenomyosis: an update on molecular mechanisms. Reprod Biomed Online. 2017; 35(5): 592–601. - 60Dong Y, Chen Y, Wang Y, Wang L, Zhou Y, Xue M, et al. Correlation between the systemic immunoinflammatory index and platelet-lymphocyte ratio in patients with adenomyosis. Mediators Inflamm. 2024; 2024:9977750. - 61Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci. 2009; 122(Pt 18): 3209–3213. - 62Critchley HOD, Maybin JA, Armstrong GM, Williams ARW. Physiology of the endometrium and regulation of menstruation. Physiol Rev. 2020; 100(3): 1149–1179. - 63Evans J, Salamonsen LA. Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord. 2012; 13(4): 277–288. - 64Guo SW. Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large? Gynecol Obstet Invest. 2007; 63(2): 71–97. - 65Donnez J, Donnez O, Tourniaire J, Brethous M, Bestel E, Garner E, et al. Uterine adenomyosis treated by linzagolix, an oral gonadotropin-releasing hormone receptor antagonist: a pilot study with a new ‘hit hard first and then maintain’ regimen of administration. J Clin Med. 2021; 10(24):5794. - 66Wang X, Benagiano G, Liu X, Guo SW. Unveiling the pathogenesis of adenomyosis through animal models. J Clin Med. 2022; 11(6):1744. - 67Walker BE. Uterine tumors in old female mice exposed prenatally to diethylstilbestrol. J Natl Cancer Inst. 1983; 70(3): 477–484. - 68Huseby RA, Soares MJ, Talamantes F. Ectopic pituitary grafts in mice: hormone levels, effects on fertility, and the development of adenomyosis uteri, prolactinomas, and mammary carcinomas. Endocrinology. 1985; 116(4): 1440–1448. - 69Singtripop T, Mori T, Shiraishi K, Park MK, Kawashima S. Age-related changes in gonadotropin, prolactin and growth hormone levels with reference to the development of uterine adenomyosis in female SHN mice. In Vivo. 1993; 7(2): 147–150. - 70Danilovich N, Roy I, Sairam MR. Emergence of uterine pathology during accelerated biological aging in FSH receptor-haploinsufficient mice. Endocrinology. 2002; 143(9): 3618–3627. - 71Ilha MR, Newman SJ, van Amstel S, Fecteau KA, Rohrbach BW. Uterine lesions in 32 female miniature pet pigs. Vet Pathol. 2010; 47(6): 1071–1075. https://doi.org/10.1177/0300985810382522 - 72Wilkinson M, Walters S, Smith T, Wilkinson A. Reproductive abnormalities in aged female Macaca fascicularis. J Med Primatol. 2008; 37(Suppl 1): 88–93. - 73Chaffee BK, Beck AP, Owston MA, Kumar S, Baze WB, Magden ER, et al. Spontaneous reproductive tract lesions in aged captive chimpanzees. Vet Pathol. 2016; 53(2): 425–435. - 74Parrott E, Butterworth M, Green A, White IN, Greaves P. Adenomyosis—a result of disordered stromal differentiation. Am J Pathol. 2001; 159(2): 623–630. https://doi.org/10.1016/S0002-9440(10)61733-6 - 75Bourdon M, Santulli P, Doridot L, Jeljeli M, Chêne C, Chouzenoux S, et al. Immune cells and Notch1 signaling appear to drive the epithelial to mesenchymal transition in the development of adenomyosis in mice. Mol Hum Reprod. 2021;(10): 27, gaab053. - 76Harmsen MJ, Juffermans LJM, Kroon MO, Griffioen AW, Huirne JAF. Anti-angiogenic therapy as potential treatment for adenomyosis. Angiogenesis. 2025; 28(1): 12. - 77Kay N, Huang CY, Yu YC, Chen CC, Chang CC, Huang SJ. The involvement of mitochondrial dysfunction during the development of adenomyosis. Am J Pathol. 2025; 195: 861–874. - 78Squatrito M, Vervier J, Bindels J, Bernet L, Blacher S, Nisolle M, et al. Impaired fertility in adenomyosis: a murine model reveals endometrial receptivity and progesterone resistance imbalances. Reproduction. 2024; 167(5):e240019. https://doi.org/10.1530/REP-24-0019 - 79Zhu B, Chen Y, Guo M, zhang C, Huang L, Pan Q, et al. Berberine attenuates hyperalgesia in mice with adenomyosis. Arch Gynecol Obstet. 2022; 306(1): 115–125. - 80Liu X, Guo SW. Valproic acid alleviates generalized hyperalgesia in mice with induced adenomyosis. J Obstet Gynaecol Res. 2011; 37(7): 696–708. - 81Mao X, Wang Y, Carter AV, Zhen X, Guo SW. The retardation of myometrial infiltration, reduction of uterine contractility, and alleviation of generalized hyperalgesia in mice with induced adenomyosis by levo-tetrahydropalmatine (l-THP) and andrographolide. Reprod Sci. 2011; 18(10): 1025–1037. - 82Zhu B, Chen Y, Shen X, Liu X, Guo SW. Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence. Reprod Biol Endocrinol. 2016; 14(1): 66. - 83Shen M, Liu X, Zhang H, Guo SW. Transforming growth factor beta1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum Reprod. 2016; 31(2): 355–369. - 84Green AR, Edwards RE, Greaves P, White IN. Comparison of the effect of oestradiol, tamoxifen and raloxifene on nerve growth factor-alpha expression in specific neonatal mouse uterine cell types using laser capture microdissection. J Mol Endocrinol. 2003; 30(1): 1–11. - 85Mehasseb MK, Bell SC, Habiba MA. The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse. Reproduction. 2009; 138(2): 341–350. - 86Cao Y, Wang X, L X, Harada T, Guo SW. Neonatal feeding of an estrogen receptor β (ERβ) agonist induces external adenomyosis-like lesions in ICR mouse. Reprod Dev Med. 2022; 6(3): 144–151. - 87Mehasseb MK, Bell SC, Habiba MA. Neonatal administration of tamoxifen causes disruption of myometrial development but not adenomyosis in the C57/BL6J mouse. Reproduction. 2010; 139(6): 1067–1075. - 88Yamashita S. Expression of estrogen-regulated genes during development in the mouse uterus exposed to diethylstilbestrol neonatally. Curr Pharm des. 2006; 12(12): 1505–1520. - 89Newbold RR, Jefferson WN, Grissom SF, Padilla-Banks E, Snyder RJ, Lobenhofer EK. Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life. Mol Carcinog. 2007; 46(9): 783–796. - 90Jefferson WN, Chevalier DM, Phelps JY, Cantor AM, Padilla-Banks E, Newbold RR, et al. Persistently altered epigenetic marks in the mouse uterus after neonatal estrogen exposure. Mol Endocrinol. 2013; 27(10): 1666–1677. - 91Yin Y, Lin C, Veith GM, Chen H, Dhandha M, Ma L. Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells. Dis Model Mech. 2012; 5(6): 870–880. - 92Suen AA, Jefferson WN, Wood CE, Padilla-Banks E, Bae-Jump VL, Williams CJ. SIX1 oncoprotein as a biomarker in a model of hormonal carcinogenesis and in human endometrial cancer. Mol Cancer Res. 2016; 14(9): 849–858. - 93Newbold RR, Jefferson WN, Padilla-Banks E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol. 2007; 24(2): 253–258. - 94Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC. Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog. 2003; 38(2): 78–84. - 95Tang WY, Newbold R, Mardilovich K, Jefferson W, Cheng RYS, Medvedovic M, et al. Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology. 2008; 149(12): 5922–5931. - 96Bredfeldt TG, Greathouse KL, Safe SH, Hung MC, Bedford MT, Walker CL. Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol. 2010; 24(5): 993–1006. - 97Guo SW. The pathogenesis of adenomyosis vis-a-vis endometriosis. J Clin Med. 2020; 9(2): 485. - 98Levgur M, Abadi MA, Tucker A. Adenomyosis: symptoms, histology, and pregnancy terminations. Obstet Gynecol. 2000; 95(5): 688–691. - 99Curtis KM, Hillis SD, Marchbanks PA, Peterson HB. Disruption of the endometrial-myometrial border during pregnancy as a risk factor for adenomyosis. Am J Obstet Gynecol. 2002; 187(3): 543–544. - 100Hao M, Liu X, Guo SW. Adenomyosis in mice resulting from mechanically or thermally induced endometrial-myometrial interface disruption and its possible prevention. Reprod Biomed Online. 2020; 41(5): 925–942. - 101Elsherbini M, Koga K, Hiraoka T, Kumasawa K, Maki E, Satake E, et al. Establishment of a novel mouse model of adenomyosis suitable for longitudinal and quantitative analysis and perinatal outcome studies. Sci rep. 2022; 12(1): 17515. - 102Zheng H, Liu M, Su Q, Li H, Wang F. Impaired fertility and perinatal outcomes in adenomyosis: insights from a novel murine model and uterine gene profile alterations during implantations. Am J Obstet Gynecol. 2025. https://doi.org/10.1016/j.ajog.2025.02.033 10.1016/j.ajog.2025.02.033Google Scholar - 103Mao C, Liu X, Guo S-W. Decreased glycolysis at menstruation delays endometrial repair and is associated with increased menstrual blood loss. Reprod Sci. 2022; 30(3): 928–951. - 104Mao C, Liu X, Guo SW. Reduced endometrial expression of histone deacetylase 3 in women with adenomyosis who complained of heavy menstrual bleeding. Reprod Biomed Online. 2023; 47(5):103288. - 105Kishi 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.e1–114.e7. - 106Abushahin N, Zhang T, Chiang S, Zhang X, Hatch K, Zheng W. Serous endometrial intraepithelial carcinoma arising in adenomyosis: a report of 5 cases. Int J Gynecol Pathol. 2011; 30(3): 271–281. - 107Mao C, Liu X, Guo SW. Reduced endometrial glycolysis concomitant with increased lesional fibrosis in patients with adenomyosis who complained of heavy menstrual bleeding. Reprod Biomed Online. 2025; 50(2):104406. - 108Kim TH, Yoo JY, Choi KC, Shin JH, Leach RE, Fazleabas AT, et al. Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med. 2019; 11(474):eaaf7533. - 109Bazot M, Darai E. Role of transvaginal sonography and magnetic resonance imaging in the diagnosis of uterine adenomyosis. Fertil Steril. 2018; 109(3): 389–397. - 110Bourdon M, Oliveira J, Marcellin L, Santulli P, Bordonne C, Maitrot Mantelet L, et al. Adenomyosis of the inner and outer myometrium are associated with different clinical profiles. Hum Reprod. 2021; 36(2): 349–357. - 111Khan KN, Fujishita A, Koshiba A, Kuroboshi H, Mori T, Ogi H, et al. Biological differences between intrinsic and extrinsic adenomyosis with coexisting deep infiltrating endometriosis. Reprod Biomed Online. 2019; 39(2): 343–353. - 112Chapron C, Tosti C, Marcellin L, Bourdon M, Lafay-Pillet MC, Millischer AE, et al. Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes. Hum Reprod. 2017; 32(7): 1393–1401. - 113Marcellin L, Santulli P, Bortolato S, Morin C, Millischer AE, Borghese B, et al. Anterior focal adenomyosis and bladder deep infiltrating endometriosis: is there a link? J Minim Invasive Gynecol. 2018; 25(5): 896–901. - 114Marcellin L, Santulli P, Bourdon M, Maignien C, Campin L, Lafay-Pillet MC, et al. Focal adenomyosis of the outer myometrium and deep infiltrating endometriosis severity. Fertil Steril. 2020; 114(4): 818–827. - 115Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Invasiveness of endometriotic cells in vitro. Lancet. 1995; 346(8988): 1463–1464. - 116Donnez J, Dolmans MM, Fellah L. What if deep endometriotic nodules and uterine adenomyosis were actually two forms of the same disease? Fertil Steril. 2019; 111(3): 454–456. - 117Guo SW. Fibrogenesis resulting from cyclic bleeding: the holy grail of the natural history of ectopic endometrium. Hum Reprod. 2018; 33(3): 353–356. - 118Zhang Q, Duan J, Liu X, Guo SW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol. 2016; 428: 1–16. - 119Liu X, Shen M, Qi Q, Zhang H, Guo SW. Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod. 2016; 31(4): 734–749. - 120Mehasseb MK, Bell SC, Pringle JH, Habiba MA. Uterine adenomyosis is associated with ultrastructural features of altered contractility in the inner myometrium. Fertil Steril. 2010; 93(7): 2130–2136. - 121Guo SW, Mao X, Ma Q, Liu X. Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor (OTR) in women with symptomatic adenomyosis. Fertil Steril. 2013; 99(1): 231–240. - 122Mechsner S, Grum B, Gericke C, Loddenkemper C, Dudenhausen JW, Ebert AD. Possible roles of oxytocin receptor and vasopressin-1alpha receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri. Fertil Steril. 2010; 94(7): 2541–2546. - 123Shi JH, Jin L, Leng JH, Lang JH. Expression of potassium channels in uterine smooth muscle cells from patients with adenomyosis. Chin Med J (Engl). 2016; 129(2): 200–205. - 124Chu LH, Liao CC, Liew PL, Chen CW, Su PH, Wen KC, et al. Epigenomic analysis reveals the KCNK9 potassium channel as a potential therapeutic target for adenomyosis. Int J Mol Sci. 2022; 23(11):5973. - 125Smith R, Imtiaz M, Banney D, Paul JW, Young RC. Why the heart is like an orchestra and the uterus is like a soccer crowd. Am J Obstet Gynecol. 2015; 213(2): 181–185. - 126Barcena de Arellano ML, Arnold J, Lang H, Vercellino GF, Chiantera V, Schneider A, et al. Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine. 2013; 62(2): 253–261. - 127Barcena de Arellano ML, Arnold J, Vercellino F, Chiantera V, Schneider A, Mechsner S. Overexpression of nerve growth factor in peritoneal fluid from women with endometriosis may promote neurite outgrowth in endometriotic lesions. Fertil Steril. 2011; 95(3): 1123–1126. - 128Greaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW, Saunders PT. Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis. Am J Pathol. 2015; 185(8): 2286–2297. - 129Yan D, Liu X, Guo SW. Endometriosis-derived thromboxane A2 induces neurite outgrowth. Reprod Sci. 2017; 24(6): 829–835. - 130Greaves E, Collins F, Esnal-Zufiaurre A, Giakoumelou S, Horne AW, Saunders PT. Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3. Endocrinology. 2014; 155(10): 4015–4026. - 131Asally R, Markham R, Manconi F. The expression and cellular localisation of neurotrophin and neural guidance molecules in peritoneal ectopic lesions. Mol Neurobiol. 2019; 56(6): 4013–4022. - 132Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod. 2009; 24(4): 827–834. - 133Wang G, Tokushige N, Russell P, Dubinovsky S, Markham R, Fraser IS. Hyperinnervation in intestinal deep infiltrating endometriosis. J Minim Invasive Gynecol. 2009; 16(6): 713–719. - 134Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids. Fertil Steril. 2010; 94(2): 730–737. - 135Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine fibroids. Fertil Steril. 2009; 92(5): 1799–1801. - 136Zhang X, Xu H, Huang X, Quinn M. Altered innervation of the fallopian tube in adenomyosis. J Obstet Gynaecol. 2015; 35(3): 319–320. - 137Nie J, Liu X, Guo SW. Immunoreactivity of oxytocin receptor and transient receptor potential vanilloid type 1 and its correlation with dysmenorrhea in adenomyosis. Am J Obstet Gynecol. 2010; 202(4): 346.e1–346.e8. - 138Chen Y, Zhu B, Zhang H, Ding D, Liu X, Guo SW. Possible loss of GABAergic inhibition in mice with induced adenomyosis and treatment with Epigallocatechin-3-gallate attenuates the loss with improved hyperalgesia. Reprod Sci. 2014; 21(7): 869–882. - 139Liu X, Yan D, Guo SW. Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis. Hum Reprod. 2019; 34(3): 452–468. - 140Yan D, Liu X, Guo SW. Neuropeptides substance P and calcitonin gene related peptide accelerate the development and fibrogenesis of endometriosis. Sci rep. 2019; 9(1): 2698. - 141Yan D, Liu X, Guo SW. Nerve fibers and endometriotic lesions: partners in crime in inflicting pains in women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2017; 209: 14–24. - 142Guo SW, Zhang Q, Liu X. Social psychogenic stress promotes the development of endometriosis in mouse. Reprod Biomed Online. 2017; 34(3): 225–239. - 143Long Q, Liu X, Qi Q, Guo SW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor beta2. Hum Reprod. 2016; 31(11): 2506–2519. - 144Yin B, Jiang H, Liu X, Guo SW. Enriched environment decelerates the development of endometriosis in mouse. Reprod Sci. 2020; 27(7): 1423–1435. - 145He W, Liu X, Zhang Y, Guo SW. Generalized hyperalgesia in women with endometriosis and its resolution following a successful surgery. Reprod Sci. 2010; 17(12): 1099–1111. - 146Huang Q, Liu X, Critchley H, Fu Z, Guo SW. How does the extent of fibrosis in adenomyosis lesions contribute to heavy menstrual bleeding? Reprod Med Biol. 2022; 21(1):e12442. - 147Liu X, Zhang Q, Guo SW. Histological and immunohistochemical characterization of the similarity and difference between ovarian endometriomas and deep infiltrating endometriosis. Reprod Sci. 2018; 25(3): 329–340. - 148Liu X, Guo SW. Aberrant immunoreactivity of deoxyribonucleic acid methyltransferases in adenomyosis. Gynecol Obstet Invest. 2012; 74(2): 100–108. - 149Liu X, Nie J, Guo SW. Elevated immunoreactivity against class I histone deacetylases in adenomyosis. Gynecol Obstet Invest. 2012; 74(1): 50–55. - 150Cozzolino M, Bulun S, De Ziegler D, Exacoustos C, Fatemi H, Garcia-Velasco JA, et al. The first Lugano workshop on the role of adenomyosis in ART. Reprod Biomed Online. 2025; 50(1):104444. - 151Cao Y, Yang D, Cai S, Yang L, Yu S, Geng Q, et al. Adenomyosis-associated infertility: an update of the immunological perspective. Reprod Biomed Online. 2025; 50:104703. - 152Novella-Maestre E, Carda C, Ruiz-Sauri A, Garcia-Velasco JA, Simon C, Pellicer A. Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium: a novel molecular target for endometriosis therapy. Biol Reprod. 2010; 83(5): 866–873. - 153Zhang Q, Duan J, Olson M, Fazleabas A, Guo SW. Cellular changes consistent with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the progression of experimental endometriosis in baboons. Reprod Sci. 2016; 23(10): 1409–1421. - 154Liu X, Nie J, Guo SW. Elevated immunoreactivity to tissue factor and its association with dysmenorrhea severity and the amount of menses in adenomyosis. Hum Reprod. 2011; 26(2): 337–345. - 155Guo SW. The role of platelets in the pathogenesis and pathophysiology of adenomyosis. J Clin Med. 2023; 12(3):842. - 156Casari M, Siegl D, Deppermann C, Schuppan D. Macrophages and platelets in liver fibrosis and hepatocellular carcinoma. Front Immunol. 2023; 14:1277808. - 157Dufeys C, Bodart J, Bertrand L, Beauloye C, Horman S. Fibroblasts and platelets: a face-to-face dialogue at the heart of cardiac fibrosis. Am J Physiol Heart Circ Physiol. 2024; 326(3): H655–H669. - 158Zhu B, Chen Y, Zhang H, Liu X, Guo SW. Resveratrol reduces myometrial infiltration, uterine hyperactivity, and stress levels and alleviates generalized hyperalgesia in mice with induced adenomyosis. Reprod Sci. 2015; 22(11): 1336–1349. - 159Nie J, Liu X. Quercetin alleviates generalized hyperalgesia in mice with induced adenomyosis. Mol Med rep. 2017; 16(4): 5370–5376. - 160Nie J, Liu X. Leonurine attenuates hyperalgesia in mice with induced adenomyosis. Med Sci Monit. 2017; 23: 1701–1706. - 161Li B, Chen M, Liu X, Guo SW. Constitutive and tumor necrosis factor-alpha-induced activation of nuclear factor-kappaB in adenomyosis and its inhibition by andrographolide. Fertil Steril. 2013; 100(2): 568–577. - 162Liu X, Yu S, Guo S-W. A pilot study on the use of andrographolide to treat symptomatic adenomyosis. Gynecol Minim Invasive Ther. 2014; 3: 119–126. - 163Fan J, Liu X, Guo SW. Hypermethylation of klotho and peroxisome proliferator-activated receptor gamma concomitant with overexpression of DNA methyltransferase 1 in adenomyosis. Reprod Sci. 2025; 32(3): 668–683. - 164Xu Y, Sun Z. Molecular basis of klotho: from gene to function in aging. Endocr Rev. 2015; 36(2): 174–193. - 165Doi S, Zou Y, Togao O, Pastor JV, John GB, Wang L, et al. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem. 2011; 286(10): 8655-65. - 166Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL. Cardioprotection by klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun. 2012; 3: 1238. - 167Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019; 179(4): 813–827. - 168Liu M, Liu X, Zhang Y, Guo SW. Valproic acid and progestin inhibit lesion growth and reduce hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. 2012; 19(4): 360–373. - 169Liu X, Guo SW. A pilot study on the off-label use of valproic acid to treat adenomyosis. Fertil Steril. 2008; 89(1): 246–250. - 170Xishi L, Lei Y, Guo SW. Valproic acid as a therapy for adenomyosis: a comparative case series. Reprod Sci. 2010; 17(10): 904–912. - 171Wu 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(4): 193–205. - 172Wu Y, Guo SW. Histone deacetylase inhibitors trichostatin A and valproic acid induce cell cycle arrest and p21 expression in immortalized human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2008; 137(2): 198–203. - 173Kawano Y, Nasu K, Li H, Tsuno A, Abe W, Takai N, et al. Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target. Hum Reprod. 2011; 26(9): 2486–2498. - 174Imesch P, Samartzis EP, Dedes KJ, Fink D, Fedier A. Histone deacetylase inhibitors down-regulate G-protein-coupled estrogen receptor and the GPER-antagonist G-15 inhibits proliferation in endometriotic cells. Fertil Steril. 2013; 100(3): 770–776. - 175Wu Y, Starzinski-Powitz A, Guo SW. Trichostatin A, a histone deacetylase inhibitor, attenuates invasiveness and reactivates E-cadherin expression in immortalized endometriotic cells. Reprod Sci. 2007; 14(4): 374–382. - 176Khan S, Ahirwar K, Jena G. Anti-fibrotic effects of valproic acid: role of HDAC inhibition and associated mechanisms. Epigenomics. 2016; 8(8): 1087–1101. - 177Winkler I, Blotnik S, Shimshoni J, Yagen B, Devor M, Bialer M. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain. Br J Pharmacol. 2005; 146(2): 198–208. - 178Moynihan AT, Hehir MP, Sharkey AM, Robson SC, Europe-Finner GN, Morrison JJ. Histone deacetylase inhibitors and a functional potent inhibitory effect on human uterine contractility. Am J Obstet Gynecol. 2008; 199(2): 167.e1–167.e7. - 179Mao C, Liu X, Guo SW. Meclizine improves endometrial repair and reduces simulated menstrual bleeding in mice with induced adenomyosis. Am J Obstet Gynecol. 2024; 231(1): 113.e1–113.e13. Citing Literature Article Metrics Total unique accesses to an article’s full text in HTML or PDF/ePDF format.More metric information Scite metrics Explore this article's citation statements on scite.ai Share QR Code Generating QR code QR code copied to clipboard! Something went wrong while generating your QR code. Please try again in a moment. If the issue persists, refresh the page or contact support. Export citation Unable to load citation data. Please try again in a moment. How to cite Elkins, L. J., & Spiegelman, M. (2021). pyUserCalc: A revised Jupyter notebook calculator for uranium-series disequilibria in basalts. Earth and Space Science, 8, e2020EA001619. https://doi.org/10.1029/2020EA001619 Download Citation If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click on download. This feature enables you to download the bibliographic information (also called citation data, header data, or metadata) for the articles on our site. Citation manager file format Use the dropdown list to choose how to format the bibliographic data you're harvesting. Several citation manager formats are available, including EndNote and BibTex. You can then copy the formatted citation (as displayed) or download it as file, to your device. If the RefWorks format is chosen, the 'Download' button will be replaced with an option to directly export to RefWorks