{"paper_id":"2dffc6a7-bc75-4f8b-8724-0c88572b7c03","body_text":"Sasamori et al. BMC Women’s Health          (2021) 21:306  \nhttps://doi.org/10.1186/s12905-021-01442-x\nCASE REPORT\nA case of adenomyosis with leiomyoma \nthat was effectively treated with relugolix \nand kamishoyosan add-on therapy\nYukifumi Sasamori, Kohei Takehara, Tsuyoshi Terashima, Takako Onodera, Keita Yatsuki, Ippei Nakagawa, \nYuko Takahashi, Haruka Nishida, Takayuki Ichinose, Haruko Hiraike and Kazunori Nagasaka*  \nAbstract \nBackground: Recently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered \nan effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe \nadenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relu-\ngolix against severe adenomyosis exists.\nCase presentation: A 49-year-old woman was referred to our hospital with acute lower abdominal pain and \nabnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. \nLeft hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she \nexperienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added \nto improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a \nsignificant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired.\nConclusions: To our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was \neffectively treated with relugolix. Although the management of adverse side effects, including hot flush and head-\nache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may \nhelp treat menopausal symptoms.\nKeywords: Leiomyoma, Adenomyosis, GnRH antagonist, Relugolix, Kamishoyosan\n© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\nUterine leiomyomas are common in Japanese women, \nalthough the incidence has not been well investigated \n[1]. In the United States and Europe, the incidence may \nbe higher than in Japan, and, possibly, more than 70% of \nwomen are affected by leiomyoma by the age of 50 years \nin the world [2, 3]. Symptomatic leiomyoma often pre -\nsents with dysmenorrhea, severe anemia, and prolonged \nabnormal uterine bleeding (AUB) [4]. Some cases are \nfrequently accompanied by adenomyosis in susceptible \nage groups [5]. Adenomyosis is a chronic inflammatory \ndisease that is associated with dysmenorrhea and severe \npelvic pain [6]. Generally, adenomyosis is noted after \n40 years of age [7]. Recently, the PALM-COEIN (polyp, \nadenomyosis, leiomyoma, malignancy, hyperplasia, coag -\nulopathy, ovulatory dysfunction, endometrial, iatrogenic, \nand not-yet-classified) classification system for AUB was \napproved by the International Federation of Gynecol -\nogy and Obstetrics [8]. Uterine leiomyoma and adeno -\nmyosis are benign conditions, however, are considered \nto be leading causes of AUB and generally, regress after \nmenopause [8]. Cases of adenomyosis with leiomyoma \nOpen Access\n*Correspondence:  nagasakak@med.teikyo-u.ac.jp\nDepartment of Obstetrics and Gynecology, Teikyo University School \nof Medicine, Tokyo, Japan\n\nPage 2 of 5Sasamori et al. BMC Women’s Health          (2021) 21:306 \nare often encountered in perimenopausal women, and \nsome coexist with endometrial hyperplasia and endome -\ntrial polyps [7, 9]. However, the pathophysiology underly-\ning the comorbidities of these diseases remains unclear. \nRecent investigations have reported certain genetic risk \nfactors for estrogen-dependent endometrial cancer [10]. \nTreatment for adenomyosis and leiomyoma in peri -\nmenopausal women should be individualized consider -\ning the symptomatology. Almost half of asymptomatic \ncases, including unaware cases, would require sustained \nfollow-up, measuring the size and location by ultrasound \nexamination [4]. Masses are occasionally misdiagnosed, \nand in such cases, magnetic resonance imaging (MRI) \nprovides additional information [11]. T2-weighted imag -\ning is often helpful in differentiating between adenomyo -\nsis and leiomyoma. Typically, adenomyosis appears as \nan ill-demarcated low-signal-intensity lesion with uter -\nine enlargement [11]. In contrast, well-circumscribed \nlesions with homogenous hypointensity can be found \nin most leiomyomas [12]. After total pelvic evaluations, \nmost women approaching perimenopausal age often \nneed to decide between surgical treatment or waiting \nfor menopause. Hysterectomy is one surgical option for \nthe management of leiomyomas [13]. The types of hys -\nterectomy vary based on surgeon training and approach \n(abdominal, laparoscopic, robot-assisted, or vaginal). \nFor an enlarged uterine mass, total abdominal hysterec -\ntomy is occasionally chosen as the standard treatment. \nRecently, laparoscopic techniques have been successfully \nadapted to the general sized uteri with fewer complica -\ntions, leading to their increased use [14]. Myomectomy is \na surgical option that aims to preserve the uterus. Some \nprocedures are performed laparoscopically with minimal \ninvasiveness. However, many women desire non-surgical \noptions. For these cases, hypoestrogenic therapy with \ngonadotropin-releasing hormone (GnRH) analogs has \nbeen widely used [15]. Recently, women with leiomyoma \nwere successfully treated for AUB and pain with relugolix \nin Japan [16, 17]. Relugolix is an oral non-peptide GnRH-\nreceptor antagonist without the flare-up symptoms com -\nmonly associated with GnRH analogs [16, 17]. In Japan, \noral relugolix was approved for improving various symp -\ntoms, including menorrhagia, lower abdominal pain, \nback pain, and anemia, based on uterine leiomyoma and \nwas covered by national insurance in March 2019 [18]. \nFew cases in the literature indicate that oral relugolix is \nnow widely used for the treatment of leiomyoma. How -\never, our search revealed no reports on the use of relu -\ngolix for treating adenomyosis, although a few studies \nhave reported using GnRH antagonists because of their \neffectiveness in treating this condition [19, 20]. Herein, \nwe describe the case of a woman with leiomyoma, who \nalso was found to have adenomyosis. We, incidentally \nfound elevated C-reactive protein levels and white blood \ncell count in response to inflammation in the uterus. To \nthe best of our knowledge, this is the first report of leio -\nmyoma with adenomyosis that was treated with relugo -\nlix. Furthermore, the side effects of relugolix induced by \nhypoestrogenic conditions were effectively relieved with \nkamishoyosan, a Japanese traditional Kampo medicine, \nas an add-on therapy with relugolix.\nCase presentation\nA 49-year-old woman, gravida 0, was referred to our hos-\npital with severe acute lower abdominal pain and AUB. \nHer general physical examination was normal apart from \npelvic pain and a distended abdomen due to an enlarged \nuterus. She had never undergone a medical assessment. \nTherefore, we first performed sampling cytology of the \ncervix and endometrium. Ultrasonography showed mul -\ntiple leiomyomas in the bicornuate bicollis uterus with \nhydrosalpinx in the left tube. The work-up revealed \nanemia, a high level of D-dimer, and inflammation. The \npatient’s laboratory results are summarized in Table  1. \nA high level of serum CA-125 was also observed. No \nTable 1 Laboratory results and serologies at the first medical \nexamination\nAlb, albumin; ALT, alanine aminotransferase; APTT, alanine aminotransferase; \nAST, aspartate aminotransferase; BUN, blood urea nitrogen; CEA, \ncarcinoembryonic antigen; Cre, creatinine; CRP , C-reactive protein; Hb, \nhemoglobin; LDH, lactate dehydrogenase; Plt, platelet; PT%, ; PT-INR, \nprothrombin time-international normalized ratio; TP , ; WBC, white blood cell\nParameter\nWBC 9.0 ×  103/µL\nHb 8.1 g/dL\nPlt 3.2 ×  104/µL\nTP 7.0 g/dL\nAlb 3.8 g/dL\nLDH 172 U/L\nBUN 9.3 mg/dL\nCre 0.65 mg/dL\nNa 138 mEq/L\nK 3.9 mEq/L\nCl 103 mEq/L\nAST 24 U/L\nALT 19 U/L\nCRP 11.45 mg/dL\nPT% 78%\nPT-INR 1.12\nAPTT 32.4 s\nD-dimer 2.4 µg/mL\nCEA 1.7 ng/mL\nCA19-9 9.9 U/mL\nCA125 111.3 U/mL\n\nPage 3 of 5\nSasamori et al. BMC Women’s Health          (2021) 21:306 \n \napparent deep vein thrombosis was observed in the legs. \nShe refused hospitalization for further examinations; \nthus, we allowed her to rest at home with oral prophylac -\ntic antibiotic administration. MRI revealed a bicornuate \nbicollis uterus with multiple leiomyomas from the cer -\nvix to the fundus, which were up to 11 cm in size. Addi -\ntionally, we detected adenomyosis, multiple hematomas \nin the uterus, and hydrosalpinx in the left tube, possibly \ninduced by endometriosis (Fig.  1). To summarize, severe \nbenign conditions were observed; however, no malignant \nlesions were detected on gynecologic examination.\nBased on these examinations and because her symp -\ntoms and laboratory data were improving compared to \nher first hospital visit, except for the continuous AUB \nwith pelvic pain, we presented her with the treatment \noptions (surgical or non-surgical) to cure her severe \nsymptoms induced by leiomyoma and adenomyosis. \nBecause her enlarged uterus had grown up to the xiphi -\nsternum, we presented hysterectomy as the first option. \nHowever, she refused and opted for non-surgical treat -\nment. We prescribed oral relugolix (40 mg/day) as main -\ntenance therapy. We assessed her condition within a \nmonth during the therapy and confirmed that her symp -\ntoms induced by the leiomyoma and adenomyosis were \nrelieved, and she remained amenorrheic. Two months \nafter the initial relugolix administration, she suffered \nfrom a hot flush with a slight headache, which was con -\nsidered to be induced by relugolix. We discussed with \nthe patient about discontinuing the relugolix therapy \nand recommended surgical treatment. After 6 months \nof treatment with relugolix, we evaluated her hip and \nspine bone mineral density measured by dual-energy \nX-ray absorptiometry, and the results were normal. We \nfound that the uterine volume had significantly decreased \non MRI, and the adenomyosis had mostly disappeared \ncompared to the baseline image (Fig.  2). We continued \nfollow-up with gynecologic examinations via ultrasonog -\nraphy, and after another 6 months, she experienced AUB \nrecurrence; however, the bleeding was less compared \nwith the baseline. The patient still desired continued alle-\nviation of symptoms by relugolix therapy with the addi -\ntion of kamishoyosan at a dose of 7.5 g/day before each \nmeal. Undesirable reported adverse events, such as itchi -\nness, rash, nausea, constipation and gastric discomfort, \nwere not found. Nothing was quantified in a QOL analy -\nsis, however, kamishoyosan clearly improved the adverse \nvasomotor effects induced by relugolix. Therefore, we \nrepeated the workup, including sampling cytology from \nthe uterus, and retreated her with oral relugolix and kam-\nishoyosan for 6 months, which is the duration confirmed \nin clinical studies. The patient is currently asymptomatic.\nDiscussion and conclusions\nUterine leiomyoma and adenomyosis are considered \nestrogen-dependent and, not surprisingly, these benign \ndiseases have overlapping symptomatology and repro -\nductive consequences [21– 23]. Both lesions can grow \nto notably large sizes; in such cases, surgery is strongly \nrecommended to patients. Recent clinical phase 3 trials \nreported that relugolix combination therapy with 1 mg \nof estradiol and 0.5 mg of norethindrone acetate signifi -\ncantly improved abnormal bleeding with minor adverse \nFig. 1 Magnetic resonance images showing an enlarged bicornuate \nbicollis uterus with diffuse adenomyosis. MRI showing bicornuate \nbicollis uterus with multiple leiomyomas, diffused adenomyosis, \nand multiple hematomas in the uterus. Size of the uterus, including \nfibroid and adenomyosis, measured 22 cm in length and nearly \n10 cm in thickness\nFig. 2 Magnetic resonance images showing a significant reduction \nof the uterus after 6 months of oral relugolix (40 mg/day). After \nrelugolix therapy for 6 months, diffused adenomyosis mostly \ndisappeared compared to the baseline. It is noteworthy that the size \nof the uterus, including fibroid and adenomyosis, shrunken to 15 cm \nin length and 8 cm in thickness\n\nPage 4 of 5Sasamori et al. BMC Women’s Health          (2021) 21:306 \nvasomotor events, including hot flushes and headaches \n[23, 23]. In our case, we did not prescribe the relugo -\nlix combination therapy, but used a traditional Japa -\nnese Kampo medicine, kamishoyosan, to ameliorate \nthe adverse vasomotor effect induced by continuous \nrelugolix administration for 2 months. Fortunately, the \npatient’s bone mineral density was unaffected by the \nprolonged administration of relugolix for more than \n6 months; future investigation is required to clarify \nthis effect. Kamishoyosan contains herbal medicines, \nincluding bupleurum root, ginger, rhizomes of Atrac -\ntylodes lancea, and Moutan bark, and is indicated for \nmenopausal symptoms, with side effects, such as hot \nflushes, shoulder stiffness, and neuropsychiatric symp -\ntoms, including depression and irritability [24]. To the \nbest of our knowledge, it is the first report to show the \neffectiveness of relugolix against both leiomyomas and \nadenomyosis with severe lower abdominal pain and \ncontinuous AUB. Relugolix significantly reduced the \nsize of leiomyoma and diminished adenomyosis (Fig.  2). \nThe adverse side effects of relugolix were also relieved \nby add-on therapy with kamishoyosan. In conclusion, \nrelugolix, an oral GnRH antagonist, should improve \nsymptoms in perimenopausal women who experience \npelvic discomfort and could serve as an option to the \nstandard therapy for leiomyoma with adenomyosis.\nAbbreviations\nAUB: Abnormal uterine bleeding; GnRH: Gonadotropin-releasing hormone; \nMRI: Magnetic resonance imaging.\nAcknowledgements\nWe thank all the members of the Department of Obstetrics and Gynecology, \nTeikyo University School of Medicine.\nAuthors’ contributions\nYS and KN performed the literature review and wrote the manuscript. KT, TT, \nTO, KY, IN, YT, HN, TI, and HH participated in the literature review. YS reviewed \nall imaging studies and prepared representative images. All authors were \ninvolved in the management of the patient. All authors read and approved \nthe final manuscript.\nFunding\nThis work was supported by a Grant-in-Aid for Scientific Research (K.N.) from \nthe Ministry of Education, Science, and Culture, Japan.\nAvailability of data and materials\nThe datasets used and/or analysed during the current study available from the \ncorresponding author on reasonable request.\nDeclarations\nEthics approval and consent to participate\nThe study was approved by the ethics committee of the medical faculty at \nTeikyo University Hospital.\nConsent for publication\nWritten informed consent was obtained from the patient for the publica-\ntion of this case report and any accompanying images. A copy of the written \nconsent is available for review by the editor of this journal.\nCompeting interests\nThe authors have no competing interests to declare.\nReceived: 16 May 2021   Accepted: 2 August 2021\nReferences\n 1. Sato F, Mori M, Nishi M, Kudo R, Miyake H. Familial aggregation of uterine \nmyomas in Japanese women. J Epidemiol. 2002;12:249–53.\n 2. Buttram VJ, Reiter RC. Uterine leiomyomas: etiology, symptomatology, \nand management. Fertil Steril. 1981;36:433–45.\n 3. Ghosh S, Naftalin J, Imrie R, Hoo W-L. Natural history of uterine fibroids: a \nradiological perspective. Curr Obstet Gynecol Rep. 2018;7:117–21.\n 4. Vilos GA, Allaire C, Laberge PY, Leyland N, Vilos AG, Murji A, et al. The \nmanagement of uterine leiomyomas. J Obstet Gynaecol Canada. \n2015;37:157–78.\n 5. Taran FA, Weaver AL, Coddington CC, Stewart EA. Characteristics indicat-\ning adenomyosis coexisting with leiomyomas: a case-control study. Hum \nReprod. 2010;25:1177–82.\n 6. 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Al-Hendy A, Lukes AS, Poindexter AN, Venturella R, Villarroel C, Critchley \nHOD, et al. Treatment of uterine fibroid symptoms with relugolix combi-\nnation therapy. N Engl J Med. 2021;384:630–42.\n 24. Slomski A. Relugolix combination therapy for uterine fibroids. JAMA. \n2021;325:1602.\n 25. Takamatsu K, Ogawa M, Higuchi T, Takeda T, Hayashi K, Mizunuma \nH. Effects of Kamishoyosan, a Traditional Japanese Medicine, on \nmenopausal symptoms: a randomized, placebo-controlled, double-blind \nclinical trial. Evid-Based Complement Altern Med. 2020; 2020.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}