How to Diagnose and Treat Adenomyosis in Patients with Endometriosis

is the age depending moment of diagnosis of adenomyosis. Better di­ agnostic methods and global adenomyo­ J Reproduktionsmed Endokrinol_Online 2018; 15 (5–6) How to Diagnose and T reat Adenomyosis in Patients with Endometriosis 264 sis awareness recently allow an earlier diagnose of the disease in very young women who still do not have actual wish of conception. In these cases a long­term treatment with low complication rates and the aim to prevent a worsening of the uterine situation is required. Surgical so­ lutions does not play an important role in these patients as the adenomyotic lesions in most of these cases are minimal and almost invisible by transvaginal ultra­ sound and MR imaging and thus surgical therapy planification is difficult. The use of low dose LNG­IUDs, which are es­ pecially designed for young nulliparous patients, could be an option. However the effectiveness of these IUDs on ade­ nomyosis related symptoms needs to be proven by prospective studies. In many cases adenomyosis is just diagnosed in correlation with ongoing diagnostic steps in infertility treatment. Thus the inmediate improvement of the uterine situation is required. This aim can be achieved by medical or surgical interventions or a combination of both. Prospective studies leading to an evi­ dence based recommendation are miss­ ing so far. In a recent literature review Dueholm gives an overview of minimal invasive treatment options including medical and surgical methods, high­ lighting treatment strategies, but also the lack of knowledge and the difficul­ ties in suggesting evidence­based treat­ ments [46]. However actual literature shows a variety of different medical and surgical possibilities in the treatment of adenomyosis regarding both groups of patients. a) Medical approach The medical therapeutic options in patients with adenomyosis have been recently reviewed by Vannuccini et al [47], Pontis et al [48] and Tsui et al [49]. Each conclude that the use of sup­ pressive hormonal treatment with high dose progestins, oral contraceptives, levonorgestrel­IUDs, GnRH agonists, aromatase inhibitors, selective estrogen receptor modulator (SERMs) and se­ lective progesteron receptor modulator (SPRM´s) are able to reduce symptoms by reduction of adenomyosis. However each therapy is related to specific side effects. Actually all medical approaches represent an off­label use as no medical solution is licensed in the specific treat­ ment of adenomyosis. In daily practice and also in literature combinations of the above mentioned medical treatment op­ tions can be found. Dienogest and other Progestins While the daily administration of 2 mg of dienogest in patients with peritoneal and deep infiltrating endometriosis is a standard procedure, the use of dienogest in patients with adenomyosis can not be adopted without further evaluation. The package insert describes the pos­ sibility of severe uterine bleedings in patients with adenomyosis while using dienogest. In 2012 Nagata el al described that adenomyosis patients treated with dienogest have a higher risk of treatment discontinuation due to bleeding disor ­ ders, especially when they are of young age, have anemia before treatment and/or have mildly supressed or unsuppressed estradiol after they started dienogest treatment [50]. Nishino et al described an acute mas­ sive uterine bleeding under dienogest treatment in a patient with adenomyosis [51]. However Hirata et al. showed that dienogest reduces adenomyosis­related pelvic pain in 15 patients with treatment for up to 24 weeks. But also in this pub­ lication 5 patients experienced metror ­ rhagia [52]. In two publications Osuga et al reported the treatment of 130 and 67 adenomyosis patients with dienogest for 52 and 16 weeks. They described an effective pain reduction but also irregular uterine bleedings as most common ad­ verse reaction. However they concluded that the treatment was well­tolerated by most of the patients [53, 54]. As possible mechanisms a reduction in proliferation, NGF expression and nerve fiber density has been shown [55]. In another study the number of natural killer cells increased in glandular structures after treatment with dienogest [56]. In conclusion dieno gest seems to signif­ icantly reduce pain in patients with aden­ omyosis, while the impact of side effects like bleeding disorders and depression on the discontinuation of the treatment should be evaluated in larger prospective and age­depending studies. Also other progestins like MPA or norethisterone acetate can reduce pain in patients with adenomyosis, but are related to side ef­ fects such as acne, edema and reduction of libido causing high withdrawal rates [57–59]. Combined Oral Contraceptives (COCs) Especially in the treatment of sympto­ matic endometriosis, the COC´s play an important role when Dienogest is not tol­ erated by the patients. The combination of low dose estrogen with dienogest can cope with the progestin­related adverse effects. COC´s also may reduce adeno­ myosis­related pain, but lead to irregular bleedings in many cases [49, 60]. How­ ever in case of adenomyosis the treatment with COC´s does not represent a specific approach, but just one more possibility in a non­evidence­based situation. Shaaban et al compared low­dose oral contracep­ tive with levonorgestrel­releasing intrau­ terine system (LNG­IUS) and showed that both approaches reduced symptoms after six month. However LNG­IUS is more effective in reducing pain and men­ strual blood loss [61]. Levonorgestrel Intrauterine Device The effectiveness of LNG­IUDs in the treatment of adenomyosis related symp­ toms has been shown in various publica­ tions [62–65]. LNG­IUDs are equal or superior in comparison with systemic progestins or oral contraceptives. LNG­ IUDs are used in young women with adenomyosis with ongoing family plan­ ning, in women with completed family planning instead of hysterectomy [66], as a maintenance therapy after adenomyosis surgery [67] and in patients with fertility treatment before assisted reproduction. In a retrospective analyze Park et al de­ scribed the treatment with LNG­IUS in patients with large uterine adenomyosis and heavy menstrual bleeding. In all pa­ tients an improvement in dysmenorrhea and menstrual bleeding has been shown. 10% of patients underwent premature LNG­IUS removal and 16.7% underwent subsequent hysterectomy [68]. However a high patient satisfaction of about 80% in women after 35 years has been shown [69]. In a prospective cohort study Li et al investigated changes in menstruation patterns and adverse effects in patients with adenomyosis treated by LNG­ IUD. During the follow­up period up to 60 month, the rate of amenorrea and shortened menstruation increased, while adverse effects decreased [70]. Lee et al showed that there is a relationship be­ tween treatment failure rate and uterine volume in the use of LNG­IUDs [71]. The incidence of spontaneous expul­ sion of the IUS is higher in patients with J Reproduktionsmed Endokrinol_Online 2018; 15 (5–6) How to Diagnose and T reat Adenomyosis in Patients with Endometriosis 265 ade nomyosis and/or uterine fibroids than in normal uterus [72] and seems to depend on the insertion technique [73] and the placement timing [74]. In the postsurgical situation Lin et al described that the use of levonorgestrel­releasing intrauterine system after conservative surgery and temporary administration of gonadotropin­releasing hormone in patients with adenomyosis, guaranteed a greater reduction of dysmenorrhea in a 24­month follow­up period than the con­ trol group without additional LNG­IUD [67]. Zhang et al reported the combina­ tion of LNG­IUD with gonadotropin­ releasing hormone analogue as a effica­ cious treatment alternative [75]. The role of levonorgestrel­releasing intrauterine systems in the treatment of adolescent or very young women with adenomyosis, especially the use of low­dose IUD’s, has to be investigated in the future. Low­ dose IUD’s with 13.5 or 19.5 mg of levonor gestrel are suitable in nulliparous women, but the approved non­contracep­ tive effects of 52 mg IUD’s can not be estimated yet for this new generation of IUDs [76]. In daily practice of fertility treatment the application of LNG­IUDs prior to assisted reproduction also plays a role, which is not yet evaluated by re­ spective studies. Gonadotropin-Releasing Hormone Ana logues Gonadotropin­releasing hormone ago­ nists also play an important role in the treatment of adenomyosis. The appli­ cation can be presurgical, postsurgical, prior to assisted reproductice techniques or as individual medical treatment ap­ proach instead of other therapies. Tan et al analyzed the value of gonadotropin­ releasing hormone agonist pretreatment before adenomyomectomy and showed that the pretreatment reduces peri­ and postoperative complications [77, 78]. The combination of gonadotropin­ releasing hormone agonist application with conservative surgery seems to re­ sult in longer durable symptom­control and better reproductive outcomes in symptomatic and subfertile patients with adenomyosis compared with gonadotro­ pin­releasing hormone treatment alone [9, 79, 80]. However Chong et al investigated the long­term efficacy of adenomyo­ mectomy with or without postoperative gonadotropin­releasing hormone agonist administration and found no differences in symptom control in both groups [81]. In infertile women with adenomyosis the treatment with gonadotropin­releasing hormone agonist is indicated before fertility treatment in order to improve the results [47, 82]. Tremellen treated four patients with repeated unsuccess­ ful in vitro fertilisation with ultra­long pituitary downregulation and reported pregnancy in all cases [83]. Mijatovic et al showed that adenomyosis had no adverse effects on IVF/ICSI outcomes in patients with endometriosis when pre­ treated with long­term downregulation [84]. Niu et al showed that in frozen em­ bryo transfer the long­term GnRH ago­ nist pretreatment increased pregnancy outcomes [85]. They compared 194 pa­ tients with down­regulation and stimula­ tion with 145 patients with stimulation only. In a recent publication Dueholm et al describe actual clinical considerations in case of adenomyosis and assisted reproductive techniques [86]. In a case series Mansouri et al demonstrated the efficacy of gonadotropin­releasing hor ­ mone agonists in adolescents with re­ fractory chronic pelvic pain, failed COC therapy and positive MR imaging for adenomyosis. The treatment improved symptoms and repeated MR imaging showed regression of the lesions [87]. Akira et al described the maintenance of therapeutic effects with low­dose long­ term gonadotropin­releasing hormone agonist therapy achieving a plasma es­ tradiol level within the therapeutic win­ dow [88]. Aromatase Inhibitors Estrogen, estrogen receptors and aro­ matase play a role in the pathogenesis of adenomyosis [89]. Thus the use of aromatase inhibitors represents another attempt in the treatment of adenomyosis and its symptoms. Badawy et al showed that aromatase inhibitors are as effective as gonadotropin­releasing hormone ago­ nists in reducing adenomyoma volumen and improving symptoms. 32 patients were randomly treated with letrozole (2.5 mg/d) or subcutaneous goserelin for 12 weeks. Interestingly two patients became pregnant during treatment with letrozole [90]. Kimura et al reported a case of simultaneous treatment of se­ vere symptomatic adenomyosis with anastrozole and gonadotropin­releasing hormone agonist. They described a re­ duction of uterine volumen by 60% after eight weeks of treatment [91]. The syn­ thesis of estrogen in adenomyotic tissues has been shown in the early 90s [92]. Its role for the pathogenesis of adenomyo­ sis, treatment approaches and the relation to malignancy arising from adenomyosis has to be shown in further investigations. Selective Progesterone Receptor Mo- dulator Selective progesterone receptor modu­ lator also seem to be able to reduce symptoms in patients with adenomyosis. However only very few publications on this topic exist so far. In a single­center retrospective observational study Gracia et al used a 12­week course of ulipristal acetate (UPA) on 41 patients with adeno­ myosis and uterine fibroids. In 90 % of the patients amenorrhea was acheived and the pain was reduced [93]. Further investigations are needed to evaluate the efficacy and safety of this approach, especially in combination with fertility treatment. Selective Oestrogen Receptor Modu- lator, Valproic Acid, Anti-platelets The- rapy This group of medicaments represent an even more experimental approach than the above mentioned. In a recent clinical trial Harada et al showed the pain reducing effect of a novel selec­ tive oestrogen receptor modulator (SR­ 16234) in patients with endometriosis and adenomyosis. Also total dysmenor­ rhea score as a secondary endpoint of the study was improved [94]. Liu et al showed in a case series that valproic acid treatment for three month in pa­ tients with confirmed adenomyosis led to a complete reso lution of dysmenor ­ rhea and an average reduction of uterine size by 26% [95, 96]. In animal models the positive influence of valproic acid, epigallocatechin­3­gallate, resveratrol, leonurine and anti­platelet therapy on adenomyosis­related pain has been shown [97–101]. Several medical treatment options exist in order to reduce adenomyosis related symptoms. The most effective and safe method, without severe side effects seems to be the use of LNG­IUD’s. The posible role of new low­dose IUDs should be in­ vestigated. In combination with fertility treatment the use of gonadotropin­releas­ ing hormone agonists prior to concep­ tion or assisted reproductive techniques J Reproduktionsmed Endokrinol_Online 2018; 15 (5–6) How to Diagnose and T reat Adenomyosis in Patients with Endometriosis 266 seems to improve pregnancy rates. How­ ever this literature review shows that data is limited and prospective, comparative studies are needed in order to find out the evidence based way. So far the medical treatment of adenomyosis especially in patients with ongoing family planning is an individual recommendation, while the situation in patients with completed fam­ ily planning is based on a large number of publications, especially regarding the LNG­IUDs. b) Surgical Approach If the family planning is completed minimally invasive total or supracervi­ cal hysterectomy can effectively treat bleeding disorders and dysmenorrhea caused by adenomyosis [82]. The lapa­ roscopic supracervical hysterectomy with intraabdominal in­bag morcellation is a surgical method with a very low risk of complications [102, 103] and can be easily combined with laparoscopic resec­ tion of peritoneal endometriosis. In case of simultaneous cervical or retrocervical adenomyosis or deep infiltrating endo­ metriosis of the retrocervical region or the parametrium the total laparoscopic hysterectomy, laparoscopically assisted vaginal hysterectomy or vaginal hyster ­ ectomy is safe and feasible [104, 105]. The global endometrial ablation offers a less invasive treatment option in patients who want to preserve the uterus. Philip et al. described the use of radiofrequency global endometrial ablation in 43 pa­ tients with adenomyosis with a 36 month follow up. The intervention was effective in the treatment of adenomyosis related symptoms, but the efficacy in control­ ling bleeding decreased over time [106]. The correlation between failure rate of endometrial ablation and adenomyosis has been described in various publica­ tions [107–110]. Thus Nakamura et al described multiple endometrial abla­ tions repeating the procedure three times achieving higher satisfaction rates in controlling adenomyosis related menor ­ rhagia [111]. Ota et al recently reported the combination of microwave endome­ trial ablation and postoperative dienogest administration [112]. The combination of endometrial ablation and LNG­IUS, especially the 13.5 and 19.5 mg versions should be investigated in patients who want to preserve the uterus and avoid side effects by hormonal treatment. If possible a reliable control of symptoms with low complication rates and without systemic hormonal side effects should be first choice in this group. However more women with adeno­ myosis wish to conceive a child in the future and hysterectomy is not the only effective therapy any longer [113]. If pa­ tients want to preserve the uterus, desire preser vation or improvement of fertility the surgical resection of focal or diffuse ade nomyosis by hysteroscopy, laparo­ scopy or open surgery also represents an individual approach. Focal subendo­ metrial or intramural cystic adeno myotic lesions and intracavitary polypoid ade­ nomyoma can be resected by bipolar or monopolar hysteroresectoscopy. New instruments with lower diameter offer a minimally invasive approach espe­ cially in very young nulliparous women. The hysteroscopic resection of submu­ cous adenomyotic lesions improves dysmenor rhea and bleeding disorders [114–117]. The influence of these sur ­ gical approaches on patients fertility requires further investigatios. However it is crucial to avoid the postsurgical for­ mation of intrauterine adhesions by IUD application or temporary insertion of a Foley catheter. Laparoscopic or abdomi­ nal surgery offer a variety of surgical techniques in patients with adenomyosis. In an actual review Younes et al analyzed 27 studies including 1398 patients. Re­ section of adenomyotic lesions is effec­ tive for symptom control and most prob­ ably for adenomyosis­related infertility. More than 75 % of patients experience improvement of symptoms. Pregnancy rates varied after surgery depending on the method and the additional medical treatment of adenomyosis [118]. Most of the surgical interventions can be realized by laparoscopy. The minimally invasive approach permits the excision of subse­ rous cystic lesions [119] and focal adeno­ myomas [120, 121]. Also laparoscopic techniques for diffuse adenomyosis with uterine artery blocking and double­flap

have been described [122–124]. Recently Kwack et al compared the lapa­ roscopic and open surgical approach in 224 cases of uterine adenomyomectomy with transient occlusion of the uterine arteries [125]. They concluded that sur ­ gery is effective to reduce symptoms re­ gardless of the approach, but laparotomy seems to be more suitable for diffuse and laparoscopy more suitable for focal ade­ nomyosis. Chong et al reported that laparoscopic or robotic adenomyomectomy are feasible and safe methods in patients with adeno­ myosis. The postsurgical administration of gonadotropin­releasing hormone ago­ nist cycles did not improve the surgical

[81]. The surgical excision of the adenomyotic tissue helps to reduce dys­ menorrhea and menorrhagia. In relation to adenomyosis­associated subfertility Kishi et al described age as a determinant in fertility outcomes. In a retrospective cohort study they analyzed pregnancy rates in 102 patients who underwent lapa­ roscopic adenomyomectomy depending on the patients age. Women 40 years only a rate of 3.7 % [126]. In 2017 Dueholm et al reviewed the reproductive outcome of patients with adenomyosis after dif­ ferent surgical approaches and in vitro fertilization [9], describing the results of different open and laparoscopic surgical techniques. The authors underlined that surgery might be helpful in matters of fertility, but the effect of surgery needs to be proven in the future. They emphasized the lack of controlled studies, the miss­ ing clear diagnostic criteria, the missing reliable information about the impact of adenomyosis in fertility, the missing correlation between fertility and stage or type of adenomyosis and the lack of a severity classification of the disease. In an actual review Rocha et al described an overall clinical pregnancy rate of 18.2% after surgical treatment of adenomyosis. The additional postoperative treatment with gonadotropin­releasing hormone agonists increased the rate up to 40 % [127]. In another recent review Tan et al described a mean pregnancy rate of 52.7% in patients after surgery for fo­ cal adenomyosis and 34.1% in patients with diffuse adenomyosis. Uterine rup­ ture was reported in no patient with focal adenomyosis, but 6.8 % of patients with surgery for diffuse adenomyosis. The authors concluded that the decision for surgery should be individual considering patients with adenomyosis with medical treatment failure and women with infer ­ tility despite assisted reproductive tech­ niques [128]. However complications should be considered and further studies are needed in order to proof the safety and effectiveness of surgical methods in patients with adenomyosis [129], includ­ ing the posible affection by concomitant endometriosis [130] and the posible J Reproduktionsmed Endokrinol_Online 2018; 15 (5–6) How to Diagnose and T reat Adenomyosis in Patients with Endometriosis 267 benefit of additional medical treatments prior to or after surgery. If patients want to avoid surgery and/or desire fertility preservation or improve­ ment different interventional methods exist and therefore are currently under

[131]. The high­intensity focused ultrasound is an alternative treatment method in focal and diffuse adenomyosis. High­intensity focused ultrasound offers symptom relief and a low rate of major and minor complica­ tions considering the specific selection criteria. Additionally patients showed high conception and live birth rates after treatment [132, 133]. The safety and effi­ cacy of the method has been evaluated in various publications highlighting also its cost­effectiveness and improvement of female sexual fuction index [134–137]. In a prospective study 54 of 68 patients treated with high­intensity focused ul­ trasound got pregnant and 21 delivered healthy babies. No uterine rupture oc­ cured [138]. However the role of high­ intensity focused ultrasound in patients who wishes to get pregnant should be further investigated. Hai et al also described the transcervi­ cal radiofrequency ablation for sympto­ matic adenomyosis as a safe and effec­ tive method. No serious complications occured, however two patients devel­ oped intrauterine adhesions [139]. Also uterine artery embolization can reduce symptoms and improve quality of life in patients with symptomatic adenomyo­ sis. In a recent meta­analysis de Bruijn et al reported an overall improvement of symptoms in 83.1 % of the patients (872/1049) [140]. Liang et al described the technique as an effective uterus­spar ­ ing option for women with adenomyosis­ related symptoms. Clinical success was achieved in 89 % of the patients (117) without major complications [141]. The impact of uterine artery embolization on fertility and pregancy requires has been recently reviewed and requires further evaluation [142]. An other non­surgical alternative in both groups of patients is the use of a levonorgestrel­IUD alone or the postsur ­ gical application as described above. A conscious or often unconscious option, due to failed diagnosis of adenomyosis, is the eschewal of any particular treat­ ment. In daily routine this seems to play a certain role also in fertility treatment, as no general treatment recommendation exists and/or no importance is attached to the presence of adenomyosis, although corresponding literature shows that the presence of adenomyosis reduces the pregnancy and birth rates after in vitro fertilization [3–6]. Prospective studies are needed in order to show which way is the best to improve fertility in patients with adeno myosis. „ Conclusion The cited data shows a wide range of different experimental attempts in order to treat adenomyosis. Recently every

seems possible but none is prov­ en in relation to effectiveness, fertility outcome, reliability and side effects. As the incidence of adenomyosis is much higher and the population much younger than we thought, and thus the impact on fertility considerable, a consensus on di­ agnosis and treatment in adenomyosis is needed. A condition for adequate treatment is the diagnosis of the uterine disease adeno­ myosis in patients with endometriosis. This can be achieved by a combination of clinical history, gynecological exami­ nation transvaginal ultrasound and ad­ ditionally MR imaging when needed. As a function of individual patients family planning and the type of adenomyosis different treatment options offer a wide range of medical and surgical treatment approaches. Prospective studies are needed in order to describe the best way for our patients in the future. „ Conflict of interest The author declares that there is no con­ flict of interest regarding the publication of this paper.

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