{"paper_id":"280d331d-2b48-4992-85b4-8ac11f4ddf5e","body_text":"Abstract\n!\nAdenomyosis is an important clinical challenge in\ngynecology and healthcare economics; in its fully\ndeveloped form, hysterectomy is often used to\ntreat it in premenopausal and perimenopausal\nwomen. Symptoms of adenomyosis typically in-\nclude menorrhagia, pelvic pain and dysmenor-\nrhea. Moreover, adenomyosis and leiomyomas\ncommonly coexist in the same uterus, and differ-\nentiating the symptoms for each pathological\nprocess can be problematic. Although it has been\nrecognized for over a century, reliable epidemio-\nlogical studies on this condition are limited, be-\ncause only postoperative diagnoses were possible\nin the past. Minimally invasive surgical tech-\nniques (endometrial ablation/resection, myome-\ntrial excision/reduction, myometrial electrocoag-\nulation, uterine artery ligation) have had limited\nsuccess in the treatment of adenomyosis, and the\nreported data for these procedures have been ob-\ntained from case reports or small case series with\nonly short follow-up times. However, newer tech-\nniques including uterine artery embolization\n(UAE) and magnetic resonance imaging guided\nfocused ultrasound (MRgFUS) show promise in\ntreating adenomyosis. The data is strongest for\nUAE; these studies have the largest patient co-\nhorts. However, none of the UAE studies were\nrandomized or controlled. Thus, despite the clini-\ncal importance of adenomyosis, there is little evi-\ndence on which to base treatment decisions. The\nobjective of this review is to summarize the epi-\ndemiology, risk factors, clinical phenotype and to\nevaluate the accrued experience with surgical and\ninterventional alternatives to hysterectomy.\nZusammenfassung\n!\nDie Adenomyosis uteri stellt eine große klinische\nHerausforderung für sowohl Gynäkologie als auch\nGesundheitsökonomie dar. Oftmals ist sie bei\nsymptomatischen prä- und perimenopausalen\nFrauen Indikation zur Hysterektomie. Typische\nSymptome der Adenomyosis uteri werden mit\nMenorrhagie, Unterbauchschmerzen und Dys-\nmenorrhö beschrieben. Bei den benignen Erkran-\nkungen des Uterus kommen die Adenomyosis\nund die Leiomyome häufig gleichzeitig vor und\nerschweren so eine eindeutige Zuordnung der\nSymptomatik. Obgleich die Erstbeschreibung der\nAdenomyosis uteri aus dem letzten Jahrhundert\nstammt, existieren zu diesem Krankheitsbild\nnach wie vor keine verlässlichen epidemiologi-\nschen Daten. Dies liegt auch in der Tatsache be-\ngründet, dass in der Vergangenheit nur eine post-\noperative Diagnose dieser Erkrankung möglich\nwar. Minimalinvasive chirurgische Therapie-\nansätze (Endometriumablation/-resektion, myo-\nmetrane Exzision/Reduktion, myometrane Elek-\ntrokoagulation, Ligatur der Aa. uterinae) haben\nnur begrenzte Erfolge in der Behandlung der Ade-\nnomyosis uteri zeigen können. Darüber hinaus\nstammt die Evidenz zu diesen Therapieansätzen\nausschließlich aus Studien mit geringen Fallzah-\nlen und Fallberichten. Dennoch zeigen neuere, in-\nterventionelle Techniken einschließlich der Ute-\nrusarterienembolisation (UAE) und der Mag-\nnetresonanztomografie-gesteuerten fokussierten\nUltraschalltherapie (MRgFUS) aussichtsreiche Er-\ngebnisse in der uteruserhaltenden Behandlung\nder Adenomyosis. Obwohl die meisten Ergebnisse\ndiesbezüglich für die UAE vorhanden sind, waren\ndiese Arbeiten weder randomisiert noch kontrol-\nliert. Trotz der großen klinischen Bedeutung der\nAdenomyosis uteri gibt es nach wie vor keine aus-\nreichende Evidenz für nachhaltige Therapieemp-\nfehlungen. Ziel dieser Übersichtsarbeit ist eine\nZusammenfassung der epidemiologischen Daten,\nAdenomyosis: Epidemiology, Risk Factors,\nClinical Phenotype and Surgical and Interventional\nAlternatives to Hysterectomy\nAdenomyosis: Epidemiologie, Risikofaktoren, klinisches Erscheinungsbild\nsowie chirurgische und interventionelle Alternativen zur Hysterektomie\nAuthors F. A. Taran 1, E. A. Stewart 2, S. Brucker 1\nAffiliations 1 Womenʼs Clinic, University Tübingen, Tübingen, Germany\n2 Department of Obstetrics and Gynecology and Surgery, Mayo Clinic, Rochester, Minnesota, USA\nKey words\nl\" adenomyosis\nl\" hysterectomy\nl\" endometrial ablation\nl\" uterine artery embolization\nl\" magnetic resonance guided\nfocused ultrasound\nSchlüsselwörter\nl\n\" Adenomyosis\nl\" Hysterektomie\nl\" Endometriumsablation\nl\" Uterusarterienembolisation\nl\" Magnetresonanztomogra-\nfie‑gesteuerte fokussierte\nUltraschalltherapie\nreceived 14. 8. 2013\nrevised 30. 8. 2013\naccepted 30. 8. 2013\nBibliography\nDOI http://dx.doi.org/\n10.1055/s-0033-1350840\nGeburtsh Frauenheilk 2013; 73:\n924–931 © Georg Thieme\nVerlag KG Stuttgart · New York ·\nISSN 0016‑5751\nCorrespondence\nDr. Florin Andrei Taran\nUniversity Tübingen\nWomenʼs Clinic\nCalwerstraße 7\n72076 Tübingen\nflorin.andrei.taran@gmail.com\n924\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nGebFra Science\n\n\nIntroduction\n!\nThe first description of the condition initially referred to as “ade-\nnomyoma” was provided in 1860 by the German pathologist Carl\nvon Rokitansky, who found endometrial glands in the myometri-\num and subsequently referred to this finding as “cystosarcoma\nadenoids uterinum” [1, 2]. The modern definition of adenomyosis\nwas provided in 1972 by Bird who stated: “Adenomyosis may be\ndefined as the benign invasion of endometrium into the myome-\ntrium, producing a diffusely enlarged uterus which microscopi-\ncally exhibits ectopic non-neoplastic, endometrial glands and\nstroma surrounded by the hypertrophic and hyperplastic myo-\nmetrium” [1].\nBecause of the widespread use of hysterectomy as the primary\ntherapeutic option, starting in the 19th century, adenomyosis\nhas never been fully characterized. Currently the designation of\nbenign uterine diseases including adenomyosis and uterine fi-\nbroids resembles the 19th century designation of “cancer” before\nthe importance of histological and molecular factors affecting\ntherapeutic response and prognosis was highlighted.\nThe development of high-resolution imaging techniques, partic-\nularly magnetic resonance (MR) imaging, has improved the pre-\noperative diagnosis of adenomyosis. On T2-weighted MR images\nof the uterus, the junctional zone myometrium can be clearly dis-\ntinguished from the endometrium and outer myometrium, and\ndiffuse or focal thickening of this zone is now recognized as one\nhallmark of adenomyosis [3]. Furthermore, both MR and trans-\nvaginal ultrasound (TVU) are valuable in characterizing adeno-\nmyosis as they can identify myometrial cysts, distorted and het-\nerogeneous myometrial echotexture and poorly defined foci of\nabnormal myometrial echotexture. However, the most predictive\nTVU finding for adenomyosis is the presence of ill-defined myo-\nmetrial heterogeneity [4]. MR imaging offers sensitivity rates of\nup to 88 % and specificity rates of up to 93 %. Studies comparing\nMR and TVU offer inconclusive data, with some studies reporting\nequivalent results, and others report the superiority of MR imag-\ning [5].\nMedications such as non-steroidal anti-inflammatory drugs and/\nor hormonal therapy (oral contraceptive pills, high-dose proges-\ntins, a levonorgestrel-releasing intrauterine device, danazol, go-\nnadotropin-releasing hormone agonists) are often used to man-\nage the symptoms of adenomyosis and to temporarily induce re-\ngression of the adenomyosis. However, many women require\nmore aggressive forms of treatment [6].\nHistorically, the most common treatment for symptomatic ade-\nnomyosis has been hysterectomy. Thus, an important factor driv-\ning innovation in adenomyosis therapies is perioperative and\npostoperative morbidity as well as the potentially lower quality-\nof-life outcome associated with hysterectomy. Moreover, hyster-\nectomy is also not appropriate in women who wish to have chil-\ndren.\nA different area driving innovation in adenomyosis therapies is\nthe high healthcare costs. Recent reports have suggested that\nhealthcare costs are higher for women with leiomyomas than\nfor unaffected women, and the costs of disability are substantial,\nin all probability because surgical therapy in the form of hyster-\nectomy procedures is the major treatment option. Hysterec-\ntomies account for most of the costs, recently estimated to exceed\n$2.1 billion annually in the United States and almost 200 mil-\nlion € in Germany [7, 8]. Nevertheless, despite the clinical impor-\ntance of adenomyosis, there is little evidence on which to base\ntreatment decisions. The objective of this review was to summa-\nrize the epidemiology, risk factors, clinical phenotype and to\nevaluate the accrued experience with surgical and interventional\nalternatives to hysterectomy.\nEpidemiology\n!\nIn the past, the diagnosis of adenomyosis was made solely based\non histological analysis. An accurate determination of its inci-\ndence or prevalence has therefore not been carried out [4]. Thus,\nestimates of the prevalence of adenomyosis vary widely, from 5\nto 70 %, with the mean frequency of adenomyosis at hysterec-\ntomy given as approximately 20 to 30 % [9 –14]. In a large series\nof consecutive laparoscopic supracervical hysterectomies per-\nformed in the Gynecological University Clinic in Tübingen, ad-\nenomyosis was diagnosed histologically in 8 % of cases (149 wom-\nen out of 1955 women), and concomitant adenomyosis and leio-\nmyomas was diagnosed histologically in 20 % of the women (398\nwomen out of 1955 women); 70 % of the women with a diagnosis\nof adenomyosis were premenopausal [15].\nThere appear to be wide variations in the incidence of adeno-\nmyosis between racial and ethnic groups and different geo-\ngraphic regions [13]. It is not clear whether this is due to patient\nfactors or differences in diagnosis [13]. In addition, with an in-\ncreasing number of hysterectomies performed as laparoscopic\nsupracervical interventions, resulting consequently in morcel-\nlated uterine specimens, the spatial arrangement of the tissue is\nmodified, leading to a different reference to the surface and mak-\ning the histological diagnosis of adenomyosis more challenging.\nFinally, the likelihood of establishing the presence of adenomyo-\nsis is directly proportional to the number of tissue samples taken,\nwith the diagnosis rate ranging from 31 to 62 % in the same uter-\nus [16].\nRisk Factors\n!\nAge\n70 to 80 % of women undergoing hysterectomy for adenomyosis\nare in their fourth and fifth decade of life and are multiparous;\nseveral studies have reported a mean age over 50 years for wom-\nen undergoing hysterectomy for adenomyosis [4, 9, 13, 14, 17 –\n22]. However, newer reports using MRI criteria for diagnosis sug-\ngest that the disease may cause dysmenorrhea and chronic pelvic\npain in adolescents and women of younger reproductive age than\npreviously appreciated [23, 24]. These reports suggest that the\nclinical age at presentation of adenomyosis may be significantly\nearlier than previously thought and that early-stage adenomyosis\nmight present a different clinical phenotype compared to late-\nstage disease.\nder Risikofaktoren, des klinischen Erscheinungsbilds der Adeno-\nmyosis uteri sowie eine Analyse der eigenen Erfahrung mit chi-\nrurgischen und interventionellen Therapiemodalitäten in der Be-\nhandlung der Adenomyosis.\n925\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nDGGG Review\n\n\nMultiparity\nA high percentage of women with adenomyosis are multiparous\n[17–19, 25, 26]. Pregnancy might facilitate the formation of ad-\nenomyosis by allowing adenomyotic foci to be included in the\nmyometrium due to the invasive nature of the trophoblast on\nthe extension of the myometrial fibers [25, 26]. In addition, ad-\nenomyotic tissue may have a higher ratio of estrogen receptors\nand the hormonal milieu of pregnancy may favor the develop-\nment of islands of ectopic endometrium [4, 13]. Alternatively,\nthere may be an increased acceptance of hysterectomy in multip-\narous women.\nPrior uterine surgery\nEvidence regarding a significantly increased risk of prior uterine\nsurgery in women with adenomyosis is inconsistent. Clinical data\nhave supported the hypothesis that adenomyosis results when\nendometrial glands invade the myometrial layer, with surgical\ndisruptions of the endometrial-myometrial border increasing\nthe risk of adenomyosis in some studies [27, 28].\nLevgur et al. and Parazzini et al. reported that patients who had\nundergone pregnancy termination via dilation and curettage\ndemonstrated higher rates of adenomyosis than women without\npregnancy terminations [14, 27]. Furthermore, Parazzini et al.\nand Taran et al. also observed higher rates of adenomyosis in\nnon-pregnant patients who had undergone dilation and curett-\nage [11, 17]. Whitted et al. observed an increased prevalence of\nadenomyosis in subjects who had had prior cesarean section\n[29]. However, other studies reported no increased rates of cesar-\nean section or any other uterine surgical procedure in women\nwith adenomyosis [12, 18, 19, 30].\nThus, it is unclear whether a history of previous uterine surgery\nis a risk factor for adenomyosis [4]. Moreover, positing a relation-\nship between surgical history and the incidence of adenomyosis\nis risky when considering the selection of surgical patients. The\npatients included in the overwhelming majority of studies were\ntreated in an era when laparotomy was commonly performed;\nthe results from these studies may well be different if they were\nconducted today [19].\nSmoking\nEvidence regarding an association between smoking and adeno-\nmyosis is controversial. On the one hand, in comparison with\nwomen who never smoked, smokers appear less likely to have\nadenomyosis [11]. This finding can be explained by hormonally\ninduced mechanisms: decreased serum levels of estrogen have\nbeen reported in smokers, and adenomyosis has been suggested\nto be an estrogen-dependent disorder [31, 32].\nAlternatively, there is also evidence that there is no association\nbetween adenomyosis and smoking [14]. Moreover, two studies\neven reported a higher rate of a history of smoking in women\nwith adenomyosis than in controls [19, 33]. Thus, the association\nbetween adenomyosis and smoking deserves further investiga-\ntion.\nEctopic pregnancy\nImplantation in a focus of adenomyosis could result in a preg-\nnancy developing within the myometrium [34, 35]. In addition,\ncigarette smoking has been shown to be an independent, dose-\nrelated risk factor for ectopic pregnancy [36]. Thus, it has been\nhypothesized that women with adenomyosis are more likely to\nhave a history of ectopic pregnancy, since adenomyosis may be a\nrisk factor for the development of intramural ectopic pregnancy\n[19, 34, 35]. Another possible explanation for the higher rate of\nectopic pregnancies in women with adenomyosis is thus the\nhigher rate of women with a history of smoking [19]. Neverthe-\nless, assumptions regarding an increased likelihood of a history of\nsmoking and ectopic pregnancy in association with adenomyosis\nare hypotheses that require additional evidence.\nDepression and antidepressant use\nNovel associations with adenomyosis found in both human and\nanimal studies include an increased risk of depression, and high-\ner antidepressant use [17, 39–41]. This association may be due to\nabnormalities in prolactin dynamics. Exposure of the murine\nuterus to increased prolactin appears to be sufficient to cause\nhistological adenomyosis and is associated with up-regulation of\nthe uterine prolactin receptor messenger RNA [37, 38].\nIn vitro studies have demonstrated that prolactin is produced by\nhuman uterine tissues including the endometrium, myometrium\nand leiomyomas and that a functional prolactin receptor is\npresent in the uterus and capable of acting as a smooth muscle\ncell mitogen [17, 42 –44]. However, in the study by Taran et al.,\ntoo few of the women with adenomyosis had serum prolactin re-\nsults to permit direct analysis of this relationship. Furthermore, it\nis possible that depression may have a common pathogenic factor\nwith adenomyosis (i.e., inflammation) [17]. Studies have showed\nthat the growth and progression of endometriosis and adeno-\nmyosis continues even in ovariectomized animals. This indicates\nthat, in addition to ovarian steroid hormones, the growth of en-\ndometriosis may be regulated by the innate immune system in\nthe pelvic environment [45].\nTamoxifen treatment\nAdenomyosis is relatively rare in postmenopausal women but a\nhigher incidence of adenomyosis has been reported in women\ntreated with tamoxifen for breast cancer [46 –49]. Tamoxifen is\nan antagonist of the estrogen receptor in breast tissue via its ac-\ntive metabolite, hydroxytamoxifen. In tissues, including the en-\ndometrium, it behaves like an agonist, and adenomyosis can de-\nvelop or be reactivated [50]. Thus, adenomyosis may be more\ncommon than is generally realized in women taking tamoxifen\nand may account for postmenopausal bleeding in these patients\n[49].\nClinical Phenotype\n!\nSymptoms of adenomyosis typically include menorrhagia, chron-\nic pelvic pain and dysmenorrhea. Until recently, the diagnosis of\nadenomyosis was rarely established prior to hysterectomy and\ntherefore, it is unsurprising that preoperative diagnosis rates of\nadenomyosis based on clinical findings are poor, ranging from 3\nto 26 % [13]. The presenting symptoms of adenomyosis are non-\nspecific and can also be observed for disorders such as dysfunc-\ntional uterine bleeding, leiomyomas and endometriosis, among\nothers. Thus, certain findings on the relationship between adeno-\nmyosis, menorrhagia, dysmenorrhea and pelvic pain are contro-\nversial [12, 13].\nOwolabi and Strickler stated in 1977 that “the common associa-\ntion of adenomyosis with more obvious pelvic disease has dimin-\nished its significance as a cause of gynaecologic symptoms. Ad-\nenomyosis is the addendum to textbook chapters on ectopic en-\ndometrium; it is the forgotten process and a neglected diagnosis ”\n[51]. Weiss et al. concluded more than three decades later that\n926\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nGebFra Science\n\n\n“adenomyosis is an incidental finding and not the source of\nsymptomatology for women that undergo hysterectomy ” [26].\nHowever, most of the data that led to these conclusions was from\nretrospective studies and, in the case of the Weiss study, from\nstudies of women late in the perimenopausal transition when\nsymptoms are likely to be on the wane. In contrast to leiomyo-\nmas, no published and validated symptom questionnaire specific\nto adenomyosis is available.\nAdenomyosis and leiomyomas commonly coexist in the same\nuterus. The incidence of concomitant adenomyosis in hysterec-\ntomy specimens of women with leiomyomas is reported to range\nbetween 15 and 57 % [10, 11, 14, 26, 52, 53]. Thus, differentiating\nthe symptoms for each pathological process can be problematic.\nFurthermore, the accurate preoperative differentiation of both\nconditions in the same uterus remains poor, even with the addi-\ntion of imaging techniques including ultrasound and magnetic\nresonance imaging [6].\nHowever, recent studies suggest that there are ways in which\nwomen undergoing hysterectomy with adenomyosis differ from\nwomen who have only leiomyomas. Women with adenomyosis\nhave been shown to have lower uterine weights, more dysmenor-\nrhea, dyspareunia, pelvic pain and more disease-specific symp-\ntoms compared to women with leiomyomas alone [18, 19].\nFurthermore, a number of features have been outlined that dis-\ntinguish women with adenomyosis and leiomyomas from wom-\nen with only leiomyomas at the time of hysterectomy. Women\nwith adenomyosis and leiomyomas reported more dysmenor-\nrhea and had an increased risk of dyspareunia and pelvic pain\ncompared to women with leiomyomas alone [18]. The finding\nthat women with adenomyosis and leiomyomas undergoing hys-\nterectomy have fewer and smaller leiomyomas suggests that ad-\nenomyosis may contribute to or synergize with leiomyomas to\nincrease symptomatology, which in turn will be treated by hys-\nterectomy [18]. Consequently, in women with symptoms that\nseem disproportionate to the level of leiomyoma disease, clini-\ncians should consider the presence of adenomyosis in the differ-\nential diagnosis [18].\nMajor limitations of these studies included their retrospective\ndesign which precluded an objective measurement of symptom\nseverity. Furthermore, racial diversity was underrepresented in\nall studies. While the incidence and prevalence of leiomyomas\nin black women has been shown to be increased and the disease\nmore severe, there is no data on racial differences for adenomyo-\nsis [54, 55].\nSurgical and Interventional Alternatives\nto Hysterectomy\n!\nHysteroscopic procedures\nEndometrial ablation/resection\nHysteroscopy has become a major diagnostic and therapeutic\ntool for uterine disorders [56]. Hysteroscopic endometrial abla-\ntion/resection has been used to treat patients with menorrhagia,\nincluding patients with adenomyosis. Endometrial ablation/re-\nsection can be performed using an yttrium aluminum garnet\n(YAG) laser, rollerball resection, or global ablation techniques\n(thermal balloon ablation, cryoablation, circulated hot fluid abla-\ntion, microwave ablation, and bipolar radiofrequency ablation).\nLevgur summarized the experience with more than 2000 pa-\ntients treated by YAG laser for abnormal bleeding in his recent re-\nview [56]. All analyzed publications underlined the risk of failure\nin patients with adenomyosis and in several cases, particularly if\nfoci penetration exceeded 2.5 mm, hysterectomy was considered\nto be unavoidable [56]. Wallwiener et al. performed endometrial\nablation combining YAG laser and an electrosurgical loop in a se-\nries of 34 symptomatic, “high-risk” patients with contraindica-\ntions for hysterectomy [57]. Endometrial ablation was successful\nin 28 of 34 cases; in this series of patients, hysterectomy, with the\nrisk of major or even lethal complications, could thus be avoided.\nHowever hysterectomy had to be performed in 2 women with ex-\ntensive adenomyosis [57].\nWood et al. analyzed the therapeutic efficacy of endometrial re-\nsection in a series of 22 patients [58, 59]. In this series, a marked\nimprovement occurred in 4 of 7 patients with adenomyosis after\nendometrial resection [58]. In the second series, endometrial re-\nsection cured menorrhagia in 12 of 15 patients but dysmenor-\nrhea in only 3 of 8 [59]. However, endometrial resection reduced\nthe need for hysterectomy to 30 % in this group of patients [59].\nHysteroscopic ablation by rollerball was first described in 1989\nusing a modified urological resectoscope [60]. The initial case se-\nries included 15 patients treated for dysfunctional uterine bleed-\ning [60]. After at least 6 months of follow-up, 10 patients had\namenorrhea or hypomenorrhea. There was one failure; the pa-\ntient underwent vaginal hysterectomy 4 months after the proce-\ndure and was found to have adenomyosis [60]. This pattern of\nfailure for rollerball ablation for patients with adenomyosis has\nbeen confirmed in several studies [61, 62].\nA large retrospective cohort study from the Mayo Clinic, Roches-\nter, MN, USA, analyzed the long-term outcomes and predictors of\noutcome for women undergoing global endometrial ablation (ei-\nther thermal balloon ablation or radiofrequency ablation) to treat\nmenorrhagia [63]. Univariate analysis (HR 1.5) showed that\nwomen with a diagnosis of adenomyosis on ultrasound who\nunderwent global endometrial ablation had an increased risk of\nfailure and required subsequent hysterectomy or repeat ablation.\nHowever, adenomyosis was not identified as an independent\npredictor of treatment failure in the final multivariable model\n[63].\nExcisional procedures\nMyometrial/adenoymoma excision\nand myometrial reduction\nFocal excision of adenomyosis can be performed if the location of\nfoci can be determined. However, unlike myomectomy, it is diffi-\ncult to expose the lesions, define margins and determine the ex-\ntent of disease and thus, the efficacy of excision remains low at\n50 % [4]. Myometrial reduction to treat symptomatic adenomyo-\nsis refers to the removal of diseased tissue from the uterus. A\nlarge proportion of the myometrium is removed and the created\nwedge defect is repaired by metroplasty. The procedure can be\nperformed by laparoscopy, mini-laparotomy or laparotomy [56,\n64]. A classic incision is made, with dissection of the uterus lon-\ngitudinally in the midline and resection of the anterior and pos-\nterior portions of the myometrium [4].\nFedele et al. evaluated reproductive performance after adeno-\nmyoma excision in a prospective, observational study of 28 wom-\nen who wished to maintain fertility [65]. Thirteen (72.2 %) wom-\nen conceived; however, seven women (38.8 %) had spontaneous\nabortions. The cumulative pregnancy rate at 36 months of fol-\nlow-up was 74.7 % with a total of 18 pregnancies, of which nine\n(50 %) ended in term deliveries [65]. The high rate of spontaneous\nabortions in this study is likely due to the large excisions needed\nwhich could have reduced the gestational capability of uterus or\n927\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nDGGG Review\n\n\ndue to residual adenomyomatous growths that could have inter-\nfered with the course of pregnancy [65].\nThe largest study on adenomyomectomy to date included 165\nwomen treated with surgery alone or with combined surgical-\nmedical treatment (surgery followed by six months ʼ administra-\ntion of a gonadotropin-releasing hormone agonist) [66]. Adeno-\nmyomectomy was performed by mini-laparotomy, ultramini-\nlaparotomy, or laparoscopy. Women in both groups experienced\nstatistically significant symptom relief, and all symptom scores\ndeclined from a mean at the end of the 2-year follow-up period;\nthe symptom-recurrence rates in the surgical-medical group\nwere statistically significantly lower than those in the surgery-\nalone group [66]. Additionally, fifty-five women became preg-\nnant, with a clinical pregnancy rate of 77.5 %, and 49 women\n(69.0 %) had a successful delivery [66].\nFujishita et al. reported a modified method of reduction surgery\nof lesions in a small series of women with imaging diagnosis of\nadenomyosis [67]. A transverse H-incision method for reduction\nsurgery was used in 6 women, and conventional reduction sur-\ngery was performed in 5 women with adenomyosis. The subjec-\ntive relief of pain was more evident in the H-incision group. There\nwas no case of pregnancy in the conventional surgery group;\nhowever, 1 patient conceived spontaneously 4 months after sur-\ngery using the H-incision approach [67].\nOsada et al. reported a new method of adenomyomectomy,\nwhereby adenomyotic tissues were excised and the uterine wall\nwas reconstructed using a triple-flap method [68]. The reported\nprocedure resulted in a reduction in symptoms and a low recur-\nrence rate and allowed over half of the women who wished to\nconceive to carry their pregnancy to term without uterine rup-\nture [68].\nOther surgical procedures\nUterine artery ligation\nOnly one study investigated the effect of laparoscopic uterine ar-\ntery ligation in 20 women with symptomatic adenomyosis [69].\nBoth uterine arteries were laparoscopically ligated with hemo-\nclips, and electrocoagulation of both uterine ovarian vessels was\nperformed. Six months postoperatively, mean uterine volume\nhad decreased between 0.4 and 74.0 %. Two of nine women\nachieved remission of the mass effect of an enlarged uterus. Thir-\nteen of 16 patients achieved bleeding control and 5 reported eu-\nmenorrhea or hypomenorrhea. Twelve of 16 patients achieved\ncontrol of dysmenorrhea and 6 were analgesia-free. However,\nnine women experienced non-menstrual pain after surgery,\nthree of whom later underwent hysterectomy. Treatment out-\ncome was rated as satisfactory by only 15 % of patients, and 45 %\nwere dissatisfied. Seventeen women would have refused the pro-\ncedure if they could make the decision again. The authors con-\ncluded that the poor satisfaction rate suggests that symptomatic\nadenomyosis may not be effectively treated by laparoscopic uter-\nine artery ligation [69].\nMyometrial electrocoagulation\nElectrocoagulation has the capacity to shrink adenomyosis by\ncausing necrosis. The technique can be carried out laparoscop-\nically to treat localized or extensive disease [70]. Myometrial\nelectrocoagulation of adenomyosis is a laparoscopic procedure\nthat can be carried out using unipolar or bipolar needles and a\ncoagulation current of 50 watts. However, the procedure is con-\nsidered to be less accurate than surgical excision because electri-\ncal conduction in abnormal tissue may be incomplete and this\ncannot be evaluated during surgery [70].\nOther interventions\nUterine artery embolization\nUterine artery embolization (UAE) for women with symptomatic\nleiomyomas was first reported in 1995 [71]. UAE is a minimally\ninvasive procedure and represents an alternative to surgery. UAE\nhas been reported to be effective in women with leiomyomas and\nis associated with high patient satisfaction rates [5]. Additionally,\nUAE is more cost-effective and has shorter recovery periods and\nless pain compared to surgical techniques [5]. Commonly re-\nported side effects of UAE are pelvic pain, nausea and fever due\nto ischemic necrosis [6]. In addition, approximately 5 % of pa-\ntients experience major complications including hemorrhage,\nunplanned surgical procedures and infection. Moreover, there\nare reports of an age-related impairment of ovarian function fol-\nlowing UAE [6].\nAdenomyosis and leiomyomas often coexist in the same uterus\nand their symptoms are often similar. Thus, performing UAE in\nwomen with leioymomas will also include patients with adeno-\nmyosis [6]. At the outset of UAE for women with symptomatic\nleiomyomas, several authors attributed unsatisfactory clinical re-\nsults to the presence of concurrent adenomyosis [72, 73]. These\nobservations reinforced the importance of a correct diagnosis be-\nfore UAE and the need to evaluate a possible negative impact of\nadenomyosis on the clinical outcome of UAE [6].\nThere are, however, a number of encouraging reports in the last\n14 years on the use of UAE for the treatment of adenomyosis\n(l\n\" Table 1). Kim et al. reported the largest study of patients who\nunderwent UAE for adenomyosis without leiomyomas; the study\nincluded 54 patients with a follow-up period of at least 3 years\n[80]. Thirty-one (57.4 %) of the 54 women who were followed up\ndemonstrated long-term success; 4 patients had immediate fail-\nure of treatment, and 19 patients had recurrence. Changes in\nmenorrhagia and dysmenorrhea scores at follow-up showed a\nsignificant relief of symptoms [80]. The time between UAE and\nthe recurrence of symptoms ranged from 4 to 48 months (mean,\n17.3 months). Five patients underwent hysterectomy because of\nsymptom recurrence. Mean reduction in volume of the uterus\nwas 26.3 % at short-term follow-up and 27.4 % at long-term fol-\nlow-up [80]. Thus, the study by Kim et al. was the first to show\nTable 1 Studies on the outcome of uterine artery embolization in the treat-\nment of adenomyosis.\nStudy, year [reference] Patients\n(n)\nSymptoms\nimproved\nn( % )\nFollow-up\n(months)\nGoodwin et al., 1999 [72] 6 3 (50) 10.2\nSiskin et al., 2001 [74] 13 12 (92) 8.2\nJha et al., 2003 [75] 9 9 (100) 12.0\nToh et al., 2003 [76] 12 3 (25) 10.9\nKim et al., 2004 [77] 43 40 (93) 3.5\nPelage et al., 2005 [78] 9 5 (55) 24.0\nKitamura et al., 2006 [79] 11 10 (91) 12.0\nKim et al., 2007 [80] 54 31 (57) 58.8\nBratby and Walker, 2009 [81] 16\n1;\n112\n13 (79)1;\n6 (56)2\n36.0\nLiang et al., 2012 [82] 17 17 (100) 6.0\nSmeets et al., 2012 [83] 40 29 (73) 65.0\n1 at 12 months follow-up; 2 at 36 months follow-up\n928\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nGebFra Science\n\n\nthat UAE has an acceptable long-term success rate in the manage-\nment of symptomatic adenomyosis.\nBratby and Walker analyzed 27 women with symptomatic ad-\nenomyosis diagnosed on MRI who underwent UAE [81]. There\nwas an initial favorable clinical response, with improvement of\nmenorrhagia in 79 % (13/16) of patients at 12 months. Follow-up\ndata was available for a total of 14 patients at 2 and 3 years after\nembolization; 45.5 % reported a deterioration in menorrhagia\nsymptoms at 3 years. The authors concluded that UAE for symp-\ntomatic adenomyosis is effective in the short-term but there is a\nhigh recurrence rate of clinical symptoms 2 years following treat-\nment [81].\nThe study with the longest follow-up (mean clinical follow-up:\n65 months) evaluated UAE in 40 consecutive women with adeno-\nmyosis, of whom 22 women had a concomitant diagnosis of leio-\nmyomas [83]. Changes in junction zone thickness were assessed\nwith magnetic resonance imaging (MRI) at baseline and again at\n3 months. During follow-up, 7 of 40 women (18 %) underwent\nhysterectomy; of the 33 women with preserved uterus, 29 were\nasymptomatic [83]. There was no association between clinical\noutcome and the initial presence of leiomyomas in addition to\nadenomyosis. Furthermore, UAE resulted in long-term preserva-\ntion of the uterus in the majority of patients and the only predic-\ntor for hysterectomy during follow-up was the initial thickness of\nthe junction zone [83].\nSeveral studies conducted on the efficacy of UAE in symptomatic\nadenomyosis have shown sustained clinical and symptomatic\nimprovements. However, none of the studies were controlled or\nrandomized. Thus, the efficacy of UAE in adenomyosis remains\nunclear, primarily because of a lack of high-quality data [84].\nLarger-scale, randomized controlled studies with longer follow-\nup times are mandatory to determine the efficacy of UAE in the\ntreatment of adenomyosis.\nMagnetic resonance-guided focused ultrasound\nMagnetic resonance-guided focused ultrasound (MRgFUS) sur-\ngery was approved by the United States Food and Drug Adminis-\ntration (FDA) as a noninvasive treatment for uterine leiomyomas\n[85]. Focused ultrasound surgery delivers a concentrated quan-\ntity of ultrasound energy to deep tissue areas without thermal ef-\nfects to surrounding tissue [86].\nThe underlying process in adenomyosis is smooth muscle hyper-\nplasia and thus, MRgFUS treatment is ideal to target such lesions\n[86]. The distinction between leiomyomas and adenomyosis is\nmade using MR imaging to show diffuse or focal thickening of\nthe junctional zone of the uterus in the presence of adenomyosis\n[86].\nInitial experience with MRgFUS to treat symptomatic adenomyo-\nsis has shown promising results [87–90]. The first patient treated\nwith MRgFUS for symptomatic adenomyosis completed the\ntreatment with no complications, had improvement of menor-\nrhagia and shrinkage of the adenomyomatous mass [87]. The pa-\ntient conceived spontaneously after the procedure, and preg-\nnancy and delivery were not affected by MRgFUS treatment\n[87]. Fukunishi et al. reported early results that indicated the safe\nand effective ablation of adenomyosis tissue by MRgFUS. The pro-\ncedure also resulted in an improvement of clinical symptoms\nduring the 6 months of follow-up [89].\nKim et al. evaluated the degree of symptom relief obtained after\ntreatment with MRgFUS in patients with adenomyosis [91].\nQuality-of-life and pain assessment questionnaires from 35\nwomen, collected on the day of treatment and up to 6 months\nafter treatment, indicated that the treatment was safe and that\nthere was a significant reduction in symptoms [91]. Nevertheless,\nalthough these reports show encouraging results for the use of\nMRgfUS to treat adenomyosis, additional studies into the safety\nand efficacy of MRgFUS for women with adenomyosis are neces-\nsary.\nConclusions\n!\nAdenomyosis is an important clinical challenge in gynecology\nand healthcare economics; in its fully developed form hysterec-\ntomy is often used to treat it in pre-menopausal and perimeno-\npausal women. Although it has been recognized for over a cen-\ntury, reliable epidemiological studies on this condition are lim-\nited, probably because in the past diagnosis was only possible\npostoperatively [13]. Symptomatic women receiving treatment\nfor adenomyosis are mostly in their fourth or fifth decade and\nmultiparous. However, the diagnosis is increasingly being made\nin younger women who wish to maintain their fertility. Thus,\nthe evolution of minimally invasive and uterine-conserving\ntherapies and the demand for these therapies requires a better\nunderstanding of the disease. Additionally, there are no evi-\ndence-based guidelines to treat adenomyosis using minimally in-\nvasive methods [6].\nMinimally invasive surgical interventions (endometrial ablation/\nresection, myometrial excision/reduction, myometrial electro-\ncoagulation, uterine artery ligation) were primarily introduced\nto treat symptomatic women with adenomyosis but have had\nlimited success in the treatment of adenomyosis. Moreover, all\nreported data are from case reports or small case series with\nshort follow-up times. Thus, although some studies have re-\nported follow-up data including pregnancy and delivery rates,\nthese procedures are not generally recommended for women\nwho wish to maintain fertility.\nOn the other hand, uterine artery embolization and magnetic\nresonance imaging guided focused ultrasound therapy have\nshown encouraging results in the treatment of adenomyosis.\nThe studies on uterine artery embolization showed the most\npromising results and were carried out in the largest patient co-\nhorts. However, none of the UAE studies were randomized or\ncontrolled. Thus, the efficacy of UAE in adenomyosis remains un-\nclear, primarily because of a lack of high-quality data. Further-\nmore, at present the American College of Obstetrics and Gynecol-\nogy and the Society of Interventional Radiology list the desire for\nfuture fertility as a relative contraindication to UAE [92]. In spite\nof all these shortcomings, the emergence of various surgical and\ninterventional therapeutic modalities for a condition that, for\ndecades, could only be solved by hysterectomy is most gratifying\n[52].\nThe ontogeny of adenomyosis is clearly important for the devel-\nopment of new alternatives to hysterectomy. Prospective ran-\ndomized and controlled studies with larger cohorts, validated\nand disease-specific symptom questionnaires, noninvasive diag-\nnostic modalities as well as new surgical and interventional al-\nternatives to hysterectomy are required to better understand ad-\nenomyosis and to avoid hysterectomy.\nFor some women with adenomyosis who have completed their\nfamily planning, hysterectomy still remains the best option.\nUnderstanding the diversity of the disease, both with regards to\npathology and symptomatology, will lead to targeted therapies in\nthe short term and prevention strategies in the longer term. Our\n929\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nDGGG Review\n\n\ngoal as researchers of benign myometrial lesions is to understand\nthe biology of these lesions and provide evidence to guide indi-\nvidualized treatment (surgery vs. lifestyle modification vs. novel\ntherapies based on research insights) in the future.\nConflict of Interest\n!\nNone.\nReferences\n1 Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Ob-\nstet Gynaecol 2006; 20: 449 –463\n2 Renner SP, Lermann J, Hackl J et al. Chronische Erkrankung. Endome-\ntriose. Geburtsh Frauenheilk 2012; 72: 914 –919\n3 Gordts S, Brosens JJ, Fusi L et al. Uterine adenomyosis: a need for uni-\nform terminology and consensus classification. Reprod Biomed Online\n2008; 17: 244 –248\n4 Garcia L, Isaacson K. Adenomyosis: review of the literature. J Minim\nInvasive Gynecol 2011; 18: 428 –437\n5 Popovic M, Puchner S, Berzaczy D et al. 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Fertil Steril 2008; 90: 2018.\ne13–2018.e15\n89 Fukunishi H, Funaki K, Sawada K et al. Early results of magnetic reso-\nnance-guided focused ultrasound surgery of adenomyosis: analysis of\n20 cases. J Minim Invasive Gynecol 2008; 15: 571 –579\n90 Polina L, Nyapathy V, Mishra A et al. Noninvasive treatment of focal\nadenomyosis with MR-guided focused ultrasound in two patients. In-\ndian J Radiol Imaging 2012; 22: 93 –97\n91 Kim KA, Yoon SW, Lee C et al. Short-term results of magnetic resonance\nimaging-guided focused ultrasound surgery for patients with adeno-\nmyosis: symptomatic relief and pain reduction. Fertil Steril 2011; 95:\n1152–1155\n92 Mohan PP, Hamblin MH, Vogelzang RL. Uterine artery embolization and\nits effect on fertility. J Vasc Interv Radiol 2013; 24: 925 –930\n931\nTaran FA et al. Adenomyosis: Epidemiology, Risk … Geburtsh Frauenheilk 2013; 73: 924 –931\nDGGG Review","source_license":"public-domain-us","license_restricted":false}