Adenomyosis: diagnostics and treatment

· Zusammenfassung Gynäkologe2020·53:683–688 https://doi.org/10.1007/s00129-020-04655-7 ©TheAuthor(s)2020 H. Krentel · R. L. De Wilde Adenomyosis: diagnosticsandtreatment

Background.A denomy osisisafr equent additional condition in patientswith endometriosisandshouldbeincludedin diagnosticandtreatmentconcepts. Objective.Descriptionofdiagnosticand therapeuticapproachesinpatientswith adenomyosisinrelationtopatientage,family planningstatus,peritonealand/ordeep endometriosisandsymptoms. Methods. The current literature on adenomyosisincludingcasereports was analyzed.Duetothelackofevidenced-based approachesthemostprobabletrends in diagnosticsandtreatmentarediscussed. Results.Adenomyosisplaysanimportant roleinfertilepatientswithdysmenorrhea, dyspareuniaandpelvicpain,withorwithout additionalperitonealordeependometriosis. Ithasanegativeimpactonfertilityandcan causeavarietyofsymptoms.The disease canbediagnosedbyaskilledexaminerand treatmentconceptsexist. Conclusion.Adenomyosiscanbediagnosed by a combinationof clinicalhistory, gynecologicalexamination,transvaginal ultrasoundandmagneticresonanceimaging. Variousmedicaland surgicaltreatment approachesareavailabletoreducesymptoms andtoincreasefertility.Thecourseofaction dependsonthefamilyplanningstatusofthe patient.

Endometriosis·Infertility·Dyspareunia· Dysmenorrhea·Transvaginalultrasound Adenomyose: DiagnostikundTherapie Zusammenfassung Hintergrund.D i eA d e n o m y o s ei s te i n e häufig auftretendeBegleiterkrankung beiPatientinnenmitEndometriose und sollteinDiagnostikundtherapeutischen Behandlungskonzeptemiteinbezogen werden. Ziel.Beschreibungderdiagnostischenund therapeutischenAnsätzebei Patienten mit Adenomyose in Bezug auf Alter, Familienplanungsstatus,Peritoneal-und/oder tiefeEndometrioseundSymptome. Methoden. Die aktuelleLiteraturzur AdenomyoseeinschließlichderFallberichte wurde analysiert.Aufgrund mangelnder evidenzbasierterAnsätzewerden die wichtigstenEntwicklungeninDiagnostikund Therapiediskutiert. Ergebnisse.D ieA d enom y osespielteine bedeutendeRollebeifruchtbarenPatien- tinnenmitDysmenorrhö,Dyspareunieund Beckenschmerzen,mitoderohnezusätzliche Peritoneal-odertiefe Endometriose.Sie wirktsichnegativaufdieFruchtbarkeitaus undkanneineVielzahlvonSymptomen verursachen.DieErkrankungkannvoneinem qualifiziertenUntersucherdiagnostiziert w er d en.F ürd ieT her apiestehend iv er se BehandlungskonzeptezurVerfügung. Schlussfolgerung.DieAdenomyosekann durch eine Kombinationaus klinischer Anamnese,gynäkologischerUntersuchung, transvaginalemUltraschallundMagnetre- sonanztomographie(MRT) diagnostiziert werden.ZurLinderungderSymptomeund zur Erhöhung der Fruchtbarkeitstehen verschiedenemedizinischeundchirurgische BehandlungsansätzezurVerfügung.Das weitereVorgehen richtetsichnachdem FamilienplanungsstatusderPatientin. Schlüsselwörter Endometriose·Infertilität·Dyspareunie· Dysmenorrhö·TransvaginalerUltraschall andcytoreductivesurgicalproceduresin diffuse adenomyosis can reduce symp- toms in patients who wish to preserve the uterus. Focal subendometrial or in- tramural cystic adenomyotic lesions and intracavitary polypoidadenomyomacan be treated by hysteroresectoscopy. New instrumentswithasmallerdiameteralso provide a minimally invasive approach in very young nulliparous women. The hysteroscopic resection of adenomyotic l e s i o n si m p r o v e ss y m p t o m s .L a r g e ri n - tramural cystic lesions should be treated by laparoscopic resection and uterine suturing ( . Fig. 6;[ 18]). The influence of these procedures on patient fertility should by further investigated. Der Gynäkologe 10 · 2020 685 Leitthema Fig. 48Bipolarmini-hysteroresectoscopic biopsytechnique.(Withpermission©H.Krentel, allrightsreserved) Endometrial ablation offers a less in- vasive treatment option in patients who wanttopreservetheuterus;however,the efficacyincontrollingbleedingdecreases over time [19]. Medicaltreatmentoptions Another treatment option is the use of a levonorgestrel intrauterine device (LNG-IUD), gestagens or combined oral contraceptives. In the subgroup of patients with ongoing family planning the medical treatment can only be an option as a pretreatment before repro- ductive procedures or as a prophylactic treatment in very young women with adenomyosis and a pregnancy wish in the future. In these cases a long-term treatment with low complication rates andtheaimtopreventaworseningofthe uterine situation is required. All med- ical therapeutic possibilities in patients with adenomyosis have been recently reviewed by various authors [20, 21]. The suppressive hormonal treatments with high dose progestins, oral con- traceptives, LNG-IUDs, gonadotropin- releasing hormone (GnRH) agonists, aromatase inhibitors, selective estrogen receptor modulator (SERM) and selec- tive progesterone receptor modulator ( S P R M )a r ea b l et or e d u c es y m p t o m s by reduction of adenomyosis; however, each of these treatments is related to specific side effects. Currently, all med- ical approaches represent an off-label use as no medical solution is licensed in the specific treatment of adenomyosis. Dienogestisabletoreduceadenomyosis- relatedpelvicpainanddysmenorrheabut iscombined with ahigh risk of irregular uterine bleeding as the most common adverse reaction. Therefore, patients treated with dienogest have a certain risk of treatment discontinuation espe- cially when they are of young age, have anemia before treatment and/or have mildly supressed or unsuppressed estra- diol after starting dienogest treatment [22]. Also, progestins such as norethis- terone acetate or medroxyprogesteron acetate can reduce pain in patients with adenomyosis but are related to side ef- fects,suchasacne,edemaandreduction of libido causing high discontinuation rates. Combined oral contraceptives represent another evidence-based ther- apeutic option. The data show a pain reduction but also bleeding disorders as the main adverse effect. The LNG- IUD seems to be the most effective option in reducing pain and menstrual blood loss [23]. The LNG-IUDs can be used in women with completed family planninginsteadofh ysterectom y ,andas amaintenancetherapyafteradenomyosis surgery. In a retrospective analysis of treatment with LNG-IUD in patients with a large uterine adenomyosis and heavy menstrual bleeding, 10% under- went premature LNG-IUD removal and 16.7% underwent subsequent hysterec- tomy[24]. Theincidenceofspontaneous expulsion of the IUD is higher in pa- tients with adenomyosis and/or uterine fibroids than in women with a normal uterus and seems to depend on the insertion technique and the placement timing. The role of LNG-releasing in- trauterine systems in the treatment of adolescent or very young women with adenomyosis, especially the use of low- dose IUDs should be investigated. The use of LNG-IUDs prior to assisted re- production also has been described but has not yet been scientifically evaluated. Another medical treatment option is the use of GnRH agonists or antago- nists. Theapplicationcanbepresurgical, postsurgical, prior to assisted repro- d u c t i v et e c h n i q u e so ra sa ni n d i v i d u a l approachinstead of other medicaltreat- ments. The presurgical treatment can reduce complications and bleeding in adenomyosis surgery. The combina- tion of GnRH agonist application with conservative surgery seems to result in longer symptom control and better reproductive outcomes in symptomatic andsubfertilepatientswithadenomyosis compared with GnRH treatment alone. In infertile women with adenomyosis the treatment with GnRH agonists is indicated before fertility treatment in order to increase pregnancy and birth rates and decrease abortion rates [25]. The efficacy of GnRH agonists in ado- lescents with refractory chronic pelvic pain, failed therapy with combined oral contraceptives and positive MR imaging for adenomyosis has been reported. The treatment improved symptoms and re- peated MR imaging showed regression of thelesions [26]. Asestrogen,estrogen receptors and aromatase play a role in the pathogenesis of adenomyosis, the therapeutic use of aromatase inhibitors is an additional option. The reduction of adenomyosis volume and symptoms has been shown; however only a few publications exist and further investiga- tions are needed. Selective progesterone receptor modulators, selective estrogen receptor modulators, valproic acid and antiplatelet treatment represent another group oftreatment options, whichneeds tobeinvestigatedbeforeusedinthedaily routine. So far, the medical treatment of adenomyosis especially in patients with ongoing family planningisanindividual recommendation, while the situation in patients with completedfamily planning is based on a large number of publi- cations, especially regarding the use of LNG-IUDs. Surgicalorcombinedtreatment options in patients with ongoingfamilyplanning Patients with adenomyosis and infertil- ityhavevarious treatment options; how- ever none of these options is evidence based.Onewaycouldbethedirectrepro- ductive approach with or without med- ical pretreatment. Another way could be the combination with uterus-sparing surgery, such as adenomyectomy or cy- toreduction. Thequestions areifsurgery hasanadditional benefitfor infertile pa- 686 Der Gynäkologe 10 · 2020 Fig. 58Laparoscopicviewofsubserouscysticadenomyosis.(Withpermis- sion,©H.Krentel,allrightsreserved) Fig. 68Transvaginalultrasoundimageofanintramuralcysticadenomyosis inpatientwithongoingfamilyplanning.(Withpermission©H.Krentel,all rightsreserved) tientswithadenomyosisandwhatwould be the right moment for surgery? In a recent literature review these options includingmedicalandsurgicalmethods, highlightingtreatmentstrategies,butalso thelackofknowledgeandthedifficulties insuggestingevidence-basedtreatments, has been discussed [27]. An important factorinthepatientselectionforsurgery is the patients age, which should be less than 39 years [28]. Additional surgery m i g h tb ea no p t i o ni ns y m p t o m a t i cp a - tients, who are not able to undergo re- productive procedures, patients with in- fertility despite in vitro fertilization and intracytoplasmic sperm injection (IVF/ ICSI)andasalastresortinextremecases of diffuse adenomyosis. Surgery might be helpful in matters of fertility but the effect of surgery needs to be proven in the future [3]. »Importantinpatientselection forsurgeryisthatpatientsshould belessthan39yearsold Inarecentreviewanoverallclinicalpreg- nancy rate of 18.2% after surgical treat- mentofadenomyosiswasdescribed. The additional postoperative treatment with GnRH agonists increased the rate up to 40%[29]. Therisksofsurgicalprocedures in adenomyosis should not be underes- timated. Thesurgerycanbedifficultand the loss of organs due to severe intra- operative bleeding has been described. Adenomyosis surgery can cause uterine rupture,postsurgicalintrauterineandin- tra-abdominal adhesions and irregular placentation. Inordertominimizecom- plications adenomyosis surgery should becarriedoutinspecializedcenterswith experienced gynecological surgeons. New minimally invasive treatmentoptions High-intensityfocusedultrasound(HIFU) and radiofrequency ablation are alter- native treatment methods for focal and diffuse adenomyosis. Both techniques provide symptom relief and a low rate of major and minor complications in patients whowish topreservethe uterus or to conceive in the future. In recent publications patients undergoing HIFU for adenomyosis showed high concep- tion and live birth rates after treatment [30] ;h o w e v e r ,t h er o l eo fH I F Ui np a - tients who wish to conceive should be further investigated. The transcervical radiofrequencyablationforsymptomatic adenomyosis has also been reported to be a safe and effective method. Also, uterine artery embolization can reduce symptoms and improve the quality of life in patients with symptomatic ade- nomyosis. The impact of uterine artery embolization on fertility and pregnancy requires further evaluation. The litera- turedescribesawiderangeoftherapeutic options, but none of them are evidence basedandinrelationtoeffectiveness,fer- tility outcome, reliability andsideeffects manyquestionsstillremainunanswered. Prospectiverandomizedtrialsareneeded inordertoshowifmedicinal,surgicalor reproductive treatment alone or a com- bination is the best way to improve fertility in patients with adenomyosis. Patientswithadenomyosisneedanindi- vidual approach with detailed diagnosis of the extent of the disease and an ac- curate planning of the medicinal and/or surgical treatment. Recommendations fordaily practice 4 A d e n o m y o s i si saf r e q u e n tb e n i g n uterine disease, 4 Dysmenorrhea, dyspareunia, pelvic pain and bleeding disorders are typical symptoms, 4 Adenomyosis has a negative impact on fertility, 4 Adenomyosis can be diagnosed by a combination of clinical history, gynecological examination and transvaginal 2Dultrasound, 4 MR imaging can be useful as an additional diagnostictool, 4 The treatment approachdependson the patient’s family planning and the typeandlocalization of thedisease, 4 Medicinal treatment and surgical resection ofadenomyosis can reduce symptoms, 4 Adenomyosis surgery should only be performedinspecializedcenters. Der Gynäkologe 10 · 2020 687 Leitthema Correspondingaddress Dr.HaraldKrentel Clinic of Gynecology, Obstetrics,Gynecological Oncologyand Senology, BethesdaHospitalDuisburg, AcademicTeachingHospital Duisburg,Germany [email protected] Compliance with ethical guidelines Conflict of interest.H.KrentelandR.L.DeWilde declarethattheyhavenocompetinginterests. Ethical standards. Forthisarticlenostudieswith humanparticipantsoranimalswereperformedby anyoftheauthors.Allstudiesperformedwerein accordancewiththeethic alstandardsindicatedin eachcase. 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1. YounesG,TulandiT(2017)Effectsofadenomyosis on in vitro fertilization treatment outcomes: ameta-analysis.FertilSteril108(3):483–490 2. Buggio L, Monti E, Gattei U, Dridi D, Vercellini P (2017) Adenomyosis: fertility and obstetric outcome. A comprehensive literature review. Minerva Ginecol. https://doi.org/10.23736/ S0026-4784.17.04163-6 3. Dueholm M (2017) Uterine adenomyosis and infertility,reviewofreproductiveoutcomeafterin vitrofertilizationandsurgery.ActaObstetGynecol Scand96(6):715–726 4.TamuraH,KishiH,KitadeM,Asai-SatoM,TanakaA, MurakamiT,MinedishiT,SuginoN(2017)Clinical outcomes of infertility treatment for women with adenomyosis in Japan. Reprod Med Biol 16(3):276–282 5 .F e r r e r oS ,C a m e r i n iG ,M e n a d aM V ,B i s c a l d iE , RagniN,RemorgidaV(2009)Uterineadenomyosis in persistence of dysmenorrhea after surgical excision of pelvic endometriosis and colorectal resection.JReprodMed54(6):366–372 6. Krentel H, CezarC, BeckerS, Di SpiezioSardo A, TanosV,WallwienerM,De WildeRL(2017)From clinicalsymptomstoMRim aging:diagnosticsteps inadenomyosis.BiomedResInt2017:1514029 7. Graziano A, Lo Monte G, Piva I, Caserta D, Karner M, Engl B, Marci R (2015) Diagnostic findings in adenomyosis: a pictorial review on themajorconcerns. EurRevMed PharmacolSci 19(7):1146–1154 8. Andres MP, Borelli GM, Ribeiro J, Baracat EC, AbraoMS,KhoRM(2018)Transvaginalultrasound for the diagnosis of adenomyosis: systematic review and meta-analysis. J Minim Invasive Gynecol25(2):257–264 9. Bazot M, Darai E (2018) Role of transvaginal sonographyandmagneticresonanceimagingin thediagnosisofuterineadenomyosis. FertilSteril 109(3):389–397 10. BenagianoG,BrosensI,HabibaM(2015)Adeno- myosis: a life-cycle approach. Reprod Biomed Online30(3):220–232 11. VandenBoschT,DueholmM,LeoneFP,ValentinL, Rasmussen CK, Votino A, Van Schoubroeck D, LandolfoC,InstalléAJ,GuerrieroS,ExacoustosC, Gordts S, Benacerraf B, D’Hooghe T, De Moor B, Brölmann H, Goldstein S, Epstein E, Bourne T, Timmerman D (2015) Terms, definitions and measurementstodescribesonographicfeatures ofmyometriumanduterinemasses: aconsensus opinion from the Morphological Uterus Sono- graphicAssessment(MUSA) group. Ultrasound ObstetGynecol46(3):284–298 12. Bazot M, Cortez A, Darai E, Rouger J, Chopier J, Antoine JM, Uzan S (2001) Ultrasonography comparedwithmagneticresonanceimagingfor the diagnosis of adenomyosis: correlation with histopathology.HumReprod16(11):2427–2433 13. Novellas S, Chassang M, Delotte J, Toullalan O, Chevallier A, Bouaziz J, Chevallier P (2011) MRI characteristicsoftheuterinejunctionalzone:from normaltothediagnosisofadenomyosis.AJRAmJ Roentgenol196(5):1206–1213 14. Di Spiezio Sardo A, Calagna G, Santangelo F, ZizolfiB,TanosV,PerinoA,DeWildeRL(2017)The roleofhysteroscopyinthediagnosisandtreatment ofadenomyosis.BiomedResInt2017:2518396 15. Dakhly DM, Abdel Moety GA, Saber W, Gad AllahSH,HashemAT,AbdelSalamLO(2016)The accuracyofhysteroscopicendomyometrialbiopsy in diagnosis of adenomyosis. J Minim Invasive Gynecol23(3):364–371 16. Jeng CJ, Huang SH, Shen J, Chou CS, Tzeng CR (2007) Laparoscopy-guided myometrial biopsy inthedefinitediagnosisofdiffuseadenomyosis. HumReprod22(7):2016–2019 17. MovillaP,MorrisS,IsaacsonK(2019)Asystematic review of tissue sampling techniques for the diagnosis of adenomyosis. J Minim Invasive Gynecol. https://doi.org/10.1016/j.jmig.2019.09. 001 18. GordtsS,CampoR,BrosensI(2014)Hysteroscopic diagnosis and excision of myometrial cystic adenomyosis.GynecolSurg11(4):273–278 19. Philip CA, Le Mitouard M, Maillet L, de Saint- HilaireP,HuissoudC,CortetM,DubernardG(2018) EvaluationofNovasureglobalendometrialabla- tioninsymptomaticadenomyosis: alongitudinal study with a 36 month follow-up. Eur J Obstet GynecolReprodBiol227:46–51 20. Vannuccini S, Luisi S, Tosti C, Sorbi F, Petraglia F (2018) The role of medical therapy in the managementofuterineadenomyosis. FertilSteril 109(3):398–405 2 1 .P o n t i sA ,D ’ A l t e r i oM N ,P i r a r b aS ,d eA n g e l i sC , Tinelli R, Angioni S (2016) Adenomyosis: a sys- tematicreviewofthemedicaltreatment. Gynecol Endocrinol32(9):696–700 22. Nagata C, Yanagida S, Okamoto A, Morikawa A, Sugimoto K, Okamoto S, Ochiai K, Tanaka T (2012)Riskfactorsoftreatmentdiscontinuation duetouterinebleedinginadenomyosispatients treated with dienogest. J Obstet Gynaecol Res 38(4):639–644 23. Imai A, Matsunami K, Takagi H, Ichigo S (2014) Levonorgestrel-releasingintrauterinedeviceused fordysmenorrhea:five-yearliteraturereview.Clin ExpObstetGynecol41(5):495–498 2 4 .P a r kD S ,K i mM L ,S o n gT ,Y u nB S ,K i mM K , Jun HS, Seong SJ (2015) Clinical experiences of thelevonorgestrel-releasingintrauterinesystem inpatientswithlargesymptomaticadenomyosis. TaiwanJObstetGynecol54(4):412–415 25. Streuli I, Dubuisson J, Santulli P, de Ziegler D, Batteux F, Chapron C (2014) An update on the pharmacological managementof adenomyosis. ExpertOpinPharmacother15(16):2347–2360 26. MansouriR,SantosXM,Bercaw-PrattJL,DietrichJE (2015) Regression of adenomyosis on magnetic resonance imaging after a course of hormonal supressioninadolescents: acaseseries. JPediatr AdolescGynecol28(6):437–440 27. DueholmM(2018)Minimallyinvasivetreatmentof adenomyosis.BestPractResClinObstetGynaecol. https://doi.org/10.1016/j.bpobgyn.2018.01.016 28. Kishi Y, Yabuta M, Taniguchi F (2014) Who will benefit from uterus-sparing surgery in adenomyosis-associatedsubfertility? FertilSteril 102(3):802–807 29. RochaTP,AndresMP,BorelliGM,AbraoMS(2018) Fertility-sparing treatment of adenomyosis in patients with infertility: a systematic review of currentoptions.ReprodSci25(4):480–486 30. Zhang L, Rao F, Setzen R (2017) High intensity focused ultrasound for the treatment of adeno- myosis: selection criteria, efficacy, safety and fertility.ActaObstetGynecolScand96(6):707–714 688 Der Gynäkologe 10 · 2020