Adenomyozisde Yaklaşım

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1 Adenomyozisde Yaklaşım
Adenomyosis is a benign gynaecological condition characterized by ectopic endometrial gland and stroma invasion of the myometrium associated by hyperplasia of the adjacent smooth muscle. it is with the advances in imaging techniques that it became clear that adenomyosis is not confined to older women but can be diagnosed in young symptomatic patients (9–13) Adenomyozisde Yaklaşım Doç. Dr. L. Cem Demirel Memorial Ataşehir Hospital IVF Department

2 Adenomyosis can either be diffuse or localized (focal), depending on the extend of myometrial invasion MRI were: 1) a myometrial mass with indistinct margins of primarily low intensity with all sequences; or 2) diffuse or local widening of the junctional zone on T2-weighted images (>12 mm) Uterine adenomyosis can be classified into two categories: focal adenomyosis, with lesions localized in the anterior or posterior wall; and diffuse adenomyosis, with lesions involving the entire uterus. there is no line of demarcation between diseased and normal tissue. Yet many such women wish to retain their uterus and some even wish to bear children

3 Semptomlar Dysmenorrhea Menorrhagia Subfertility
In the majority of patients, the common triad of symptoms is dysmenorrhea, abnormal uterine bleeding, and an enlarged, tender uterus. However, 35% of adenomyotic cases are asymptomatic (1). Infertility is a less common symptom but is increasingly observed in clinical practice, as more women delay their first pregnancy until later in life. Consequently, adenomyosis is more frequently encountered in the fertility clinic during diagnostic workup.

4 Ajunctional zone thicker than 12mm is considered the golden criterion for establishing the presence of adenomyosis (1). JZ thickening (white arrow) predominates in the posterior myometrium, suggesting asymmetric adenomyosis. (B) Coronal T2-weighted image through the endometrial cavity demonstrates multiple white dots corresponding to subendometrial cysts that can be seen in the upper and right myometrial wall. (C) Sagittal T1-weighted image, through the same level as in image A, with fat suppression where blood appears white, demonstrates that two of the subendometrial cysts contain blood owing to hyperintensity. MRI enables the identification of a region in the IM with distinct signal density on T2- weighted images compared with the endometrium and the outer myometrium (OM) (14). This region has been variably coined uterine junctional zone (JZ), archimyometrium, IM, endometrial-myometrial interphase, transitional zone, or subendometrial myometrium The uterine JZ appears as a distinct low-intensity myometrial band on MRI (16) and is often seen as a subendometrial halo on high-resolution ultrasound (17 The extent of adenomyosis varies from simple JZ thickening to more diffuse or nodular lesions involving the entire uterine wall. It can also take the form of a focal adenomyoma (21). The diagnostic criteria and cutoff point for the diagnosis of adenomyosis remain controversial. A normal JZ is between 5 and 12 mm thick on T2-weighed MRI, and features highly predictive of histological adenomyosis include JZ measuring >12 mm and hemorrhagic high-signal myometrial spots (22)

5 Tanıda sonografi kriterleri
Uterusun globular konfigürasyonu Endometrium – myometrium sınırında düzensizlik, belirsizlik Subendometrial ekojenik lineer strialar Myometriumda ön arka duvar asimetrisi İntramyometrial kistler Heterojen myometrial eko It seems, therefore, that a diagnosis of adenomyosis can be made when one or more of the following sonographic findings are present: [1] a globular uterine configuration; [2] poor definition of the endometrial-myometrial interface; [3] subendometrial echogenic linear striations; [4] myometrial anterior-posterior asymmetry; [5] intramyometrial cysts; [6] a heterogeneous myometrial echo texture (30). Additional preliminary data seem to indicate that 3D TVU may be more accurate during the luteal phase (31).

6 En sensitive 2D özelliği:
Heterojen endometrium Sensitivite % 88 Accuracy % 75 En spesifik 2D özelliği: Myometrial kistler Specifisite % 98 Accuracy % 78 In fact, experts in imaging have affirmed that TVS and MRI are similarly accurate as methods for diagnosing adenomyosis (4, 9, 11–14), though TVS is a more cost-effective, less invasive, and more readily available tool for obstetricians and gynecologists. There are several studies that suggest comparable diagnostic accuracy between MRI and TVU. A systematic review and a meta-analysis of data obtained with TVU and/or MRI with histological confirmation of adenomyosis (Table 1) concluded that both techniques showed high levels of accuracy. The advantage of MRI is that images produced are standard and unaffected by the presence of fibroids

7 Exacoustos C, et Ultrasound Obstet Gynecol 2011
2 D 3 D Accuracy % 83 % 89 Sensitivity % 75 % 91 Specificity % 90 % 88 PPV % 86 % 85 NPV % 82 % 92 More recently, evaluations were made of the use of three-dimensional (3D) ultrasound, which enables assessment of the lateral and fundal aspects of the JZ and provides clearer visualization of endometrial protrusion into the myometrium (28). Using 3D TVU, the best markers are related to the JZ myometrium. A difference (JZdi) of R4 mm between the area of maximum thickness (JZmax) and the area of minimum thickness (JZmin) and its distortion and infiltration had high sensitivity (88%) and best accuracy (85% and 82%, respectively). Exacoustos C, et Ultrasound Obstet Gynecol 2011

8 İnfertilite Adenomyozis ve subfertilite arasındaki nedensel ilişki teyid edilememiştir Adenomyozisli kadında subfertilitenin insidansı tanımlanmamıştır Endometriozisle yakın birliktelik – vakaların % 54-90’ ında There is no consensus on the appropriate management of symptomatic adenomyosis in women seeking fertility. This is because: Given that adenomyosis is widely held to be a condition associated with multiparity, some authors argue that it is unrelated to subfertility Another confounding variable is the strong association between adenomyosis and endometriosis, reported to exist in 54%–90%of cases. Some authors believe that the two conditions represent different stages of the disease, whereas others identify them as separate entities (4, 19). For this reason, themechanismsleading to adenomyosis-associated infertility have been explained in similar physiopathological terms to those of endometriosis (20–24). More recently, it has been suggested that an inadequate blood supply to the endometrium interferes with implantation (25, 26), but functional studies addressing the effects of adenomyosis on endometrial receptivity are scarce

9 LIF The endometrium becomes receptive for a limited period, between 5 and 10 days after the LH surge (2). Leukemia inhibitory factor (LIF) is among many factors produced by the endometrium during this windowof implantation. Thus, LIF has been proposed as a molecular marker of receptive endometrium (3–5). Leukemia Given this result, it is possible that adenomyosis may influence hormonal and immunologic environments enough to decrease receptivity of theLeukemia inhibitory factor mRNA and protein both showed significantly lower levels in patients with adenomyosis, especially in those with a history of infertility. It might be speculated that patients with adenomyosis with a history of infertility may be associated with impaired implantation. eutopic endometriuminhibitory factor is a pleiotropic cytokine of the interleukin-6 family,

10 Endometriozis – Adenomyozis Birlikteliği
Endometriozisli kadınların % 27 sinde eş zamanlı adenomyozis mevcuttur (Bazot M, HR 2006) Endometriozisi olan infertil bir hasta grubunda adenomyozis oranı % 70 dir (Kunz G, HR 2005) Şiddetli dismenore ve derin disparuni tarifleyen endometriozisli hastaların % 42.7 sinde adenomyozis de bulunmaktadır (Gonzales M, Gynecol Surgery 2012) A common pathogenesis for adenomyosis and endometriosis has been hypothesized (98–100), and it was argued that endometrial stroma being in direct contact with the underlying myometrium allows communication and interaction, thus facilitating endometrial invagination or invasion of a structurally weakened myometrium during periods of regeneration, healing, and reepithelization (101). Mechanical damage (41, 102) to and/or physical disruption of the endometrial-myometrial interface may be due to dysfunctional uterine hyperperistalsis and/or dysfunctional contractility of the subendometrial myometrium. Dislocation of basal endometrium may also result in endometriosis through retrograde menstruation

11 Adenomyozisde Endometrial Gen Ekspresyonu
We have analyzed the functional genomics of the endometrium during the window of implantation so as to detect differences in gene expression between women with adenomyosis. In this way, we have taken advantage of the most accurate method of determining the molecular profile of endometrial receptivity. The gene expression profile of the samples obtained on LHş7 (window of implantation) did not differ between women with adenomyosis and healthy subjects using parametric tests. With nonparametric tests, only 34 genes were found to be differentially expressed (dysregulated) in women with adenomyosis (Table 1). Once a follicle of 17–18 mm was detected, LH was determined in urine samples using a commercial kit (Felcontrol, Laboratorios Effik). Endometrial biopsies were collected from the uterine fundus 7 days after the LH peak (LHş7) under sterile conditions, using a Pipelle catheter (Genetics). Rank product revealed that 25 genes were upregulated and 9 genes were downregulated in the adenomyosis group. Finally, after identifying the 25 window of implantation genes strongly related with endometrial receptiveness and the implantation process (40), it was discovered that none of them were dysregulated in the women with adenomyosis. Real-time polymerase chain reaction results validated the tendency of the gene expression values

12 Adenomyozis: İmplantasyonu Bozar mı?
Despite the frequency of adenomyosis in infertile women, not a single study has been performed to analyze how this condition affects endometrial function and, as a consequence, implantation The data showed no statistical difference among the groups in number of donated oocytes, number of blastomeres on day 3, or other parameters of embryo quality (see Table 3). Furthermore, the number of available and transferred embryos was not statistically different among the groups. Implantation and clinical pregnancy rates did not differ in the adenomyosis and adenomyosis ş endometriosis groups with respect to the control group. However, women with adenomyosis alone showed a significantly (P<.05) higher rate of miscarriage (13.1%) than those with endometriosis (6.1%) and controls (7.2%). As a result, term pregnancy rate was significantly (P<.05) lower in the adenomyosis group (26.8%) than in the adenomyosis ş endometriosis (38.0%) and control (37.1%) groups. The results showed that women with adenomyosis alone had similar implantation and pregnancy rates as those in the other two groups. However, early miscarriage was significantly higher and the rate of term pregnancy was, consequently, lower in the former group. However, it becomes apparent that women with adenomyosis have a background predisposition to higher rates of miscarriage seen after ET. A plausible mechanism for intramural fibroids that do not distort the cavity but affect the early pregnancy steps could be a disruption of the junctional zone within the myometrial layer that affects general uterine function in the initial stages of embryo invasion and later placentatio In summary, the endometrial gene expression profile of women with adenomyosis does not differ with the gene expression pattern of the controls. Furthermore, the genes involved in the implantation process or those related with the endometrial receptivity previously described are not affected. On the other hand, clinical data corresponding with miscarriage were significantly higher in the adenomyosis group because of unknown molecular mechanisms probably related with the early invasive process or the establishment of pregnancy. A careful analysis of women with adenomyosis as the sole entity present in the pelvis to explain infertility has shown that embryo implantation is not affected in oocyte donation. Thus, if adenomyosis is associated with infertility, its mechanism cannot be explained by impaired implantation. Similarly, in women with adenomyosis oocyte donation can be indicated with the same prognosis than other patients undergoing this method of assisted reproduction

13 Adenomyosis – Over cevabı / IVF outcome
kontrol p Folikül sayısı 7.21 8.99 .001 Toplanan oosit sayısı 7.75 10.15 Klinik PR % 25 33 NS Düşük oranı % 13.9 5.7 .004 Canlı doğum oranı % 12.5 24.12 .0023 These findings remained significant despite controlling individually or in combination for age, male factor infertility and the presence of endometriosis, endometriomas, fibroids or hydrosalpinx. CONCLUSION: The presence of adenomyosis diagnosed by tertiary ultrasound is associated with reduced ovarian response and live pregnancy birth rate in IVF/ET. The lower live birth rate seen with adenomyosis may occur as the result of poorer ovarian response and a higher miscarriage rate Fernandes et al ASRM , 2013

14 Adenomyozis – IVF sonuçları
Tartışmalı Down regülasyonun uzatılmasının (ultralong), adenomyozisli hastlarda faydalı olduğuna dair literatür... Mijatovic et al, Eur J Obstet Gynecol 2010 Costello et al, Eur J Obstet Gynecol Reprod Biol, 2011 Endometrial perfüzyonu artırıcı tedbirler .... Aspirin ?? The impact of adenomyosis on in vitro fertilization (IVF) treatment outcomes is controversial (10–14). Two studies showed a positive effect of prolonged down-regulation on IVF outcomes of women with adenomyosis (10, 11), whereas another study reported a negative effect of adenomyosis on the final outcome of IVF treatment

15 Tıbbi tedavi Progestogenik ajanlar etkisiz GnRH-a adenomyozisde etkili
HDACI (histone deacetylase inhibitors) ajanları (trichostatin A, valporic acid) Although the disease is hormone sensitive, progestogenic agents are ineffective. GnRH agonists induce suppression of adenomyosis, yet their use is restricted by short duration (4). In addition, the symptoms reappear after discontinuation of GnRH-agonist therapy (5). Adenomyosis and endometriosis share a great deal of similarities, in terms of definition, estrogen dependency, and symptomatology, and adenomyosis previously was considered a variant of endometriosis (6). Persistent dysmenorrhea and nonmenstrual pain after optimal surgical removal of endometriotic lesions may indicate adenomyosis (7). Evidence is converging that endometriosis, defined as the presence of heterotopic endometrial glands and stroma outside of the uterus, is an epigenetic disease (8) with aberrant methylation (9, 10) and may thus be ameliorated by demethylation agents and histone deacetylase inhibitors (HDACIs) Indeed, it recently has been reported that trichostatin A, a potent HDACI, suppresses proliferation of endometrial stromal cells (12). Further research indicates that endometriotic cells are in fact more than 100-fold more sensitive than endometrial cells to trichostatin A treatment (Wu and Guo, unpublished observation). In addition, trichostatin A suppresses IL-1–induced COX-2 expression (13), and both trichostatin A and valproic acid (VPA) induce cell-cycle arrest in endometrial cells Some circumstantial evidence suggests that adenomyosis may also be an epigenetic disease, just like endometriosis. For example, a recent study finds that retinoblastoma (pRb) is undetected in adenomyosis (14), which may result from pRb promoter hypermethylation (15). There is compelling reason to believe that HDACIs may be a promising class of compounds for treating endometriosis and perhaps adenomyosis as well. Valproic acid is a specific and potent HDACI (16, 17), with known and favorable pharmacokinetic properties. It has been used safely for 2 decades to treat epilepsy and, more recently, bipolar disorders (18, 19).

16 Within the adenomyotic tissue, there was a reduction in the expression of PR-A and PR- B in all layers. Progesterone induces an antiproliferative activity through its receptors (2, 4, 45, 46) by regulating the expression of ER-a (34, 47). The observed reduction in PR expression might explain the poor response to progestational agents (48–50), and the common presence of endometrial and myometrial hyperplasia. Despite the lower levels of PR in adenomyosis, there is evidence of favorable response to high dose local progesterone (51). Our findings are in agreement with a previous immunohistochemical study that showed a similar reduction in PR-B expression in adenomyosis (52). The same group reported hypermethylation of the PR promoter in adenomyotic endometrial stromal cells (53). This suggests that adenomyosis may be an epigenetic disease amenable to rectification by pharmacologic means by use of demethylation agents (53) such as valproic acid (54) Such reductions in PR-A and PR-B expression would potentially result in reduced expression of implantation-related genes (57). Thus, the abnormal expression of estrogen and progesterone receptor isoforms in the endometrium and myometrium of women with uterine adenomyosis suggests an overall uterine defect that contributes to its pathogenesis, symptomatology, and resistance to medical treatment

17 Adenomyozisde dysperistalsis ve dismenore patogenezinde oxytocin reseptörünün rolü
Oxytocin receptor overexpression in MSMCs may be responsible for increased uterine contractility and adenomyosisassociated dysmenorrhea. Both histone deacetylase inhibitors and andrographolide are therapeutically promising In addition, we show that the elevated myometrial OTR expression is associated with, and likely attributable to, increased uterine contractility because uterine contractions of the junctional zone in the nonpregnant uterus are oxytocin-dependent we show that treatment of myometrial smooth Muscle cells derived from adenomyotic patients with either TSA or Andro can significantly reduce the expression of OTR, leading, possibly, to normalized uterine contractility and pain alleviation This study further establishes that OTR overexpression in the myometrium is associated with increased uterine contractility in women with adenomyosis and also is associated with the dysmenorrhea severity in these women. The increased uterine contractility as a result of OTR overexpression in the myometrium, coupled with increased innervation in endometrium and myometrium in women with adenomyosis (5) and elevated expression of pain mediators/integrators such as transient receptor potential vanilloid type 1 Indeed, histone deacetylase inhibitors are shown to repress NF-kB DNA binding and suppress the expression of proinflammatory genes in human myometrial cells (56). Aside from having an excellent safety profile and besides being antiproliferative nd anti- inflammatory (57–59), valproic acid or other histone deacetylase inhibitors may also be antidysperistaltic and antinociceptive, a feature that perhaps no other compounds have as far as adenomyosis is concerned

18 Nonsurgical Options Uterine artery embolization
% 83 improvement % 64 long term satisfaction Minimal complications Popovic et al, (review) J Vasc Interv Radiol 2011; 22 MRI-guided (or ultrasound) focused ultrasound ablation LNG-IUS Similar Hb levels and better health related Q-life compared to hysterectomy Özdeğirmenci er al, FS, 2011 For patients who decline or are not suitable for surgical procedures, radiological procedures such as uterine artery embolization (UAE) or MRIguided focused ultrasound ablation can be considered. A systematic review summarized the outcomes of 15 studies where UAE was used to treat adenomyosis [33&]. Pooled short-term results of 102 patients found improvement in 83.3%. Longterm satisfaction of 208 patients was 64.9% and complications were minimal. iThe experience gathered so far with UAE has not shown eVect on fertility. However, one study focused speciWcally on this issue reporting on eight pregnancies in 94 women undergoing the procedure for leiomyoma or adenomyosis; six were in women planning pregnancy and two in whom contraception failed [108. no deWnite answer could be oVered to the question of future fertility in patients undergoing UAE for adenomyosis. Finally, a study comparing the outcomes of 74 women randomized to the levonorgestrel intrauterine system (LNG-IUS) or a hysterectomy for the treatment of adenomyosis showed that at 1-year follow-up haemoglobin levels were comparable in both groups, and women with the IUS reported slightly better health-related quality-oflife variables compared to the hysterectomy group [35&&]. These women were only followed up for 1 year, so long-term benefits are not known; however, the LNG-IUS should always be used as a first-line treatment for such women complaining of menorrhagia The levonorgestrel IUD may be used to control menorrhagia and dysmenorrhoea. If this fails endometrial ablation may be used

19 Unlike ultrasound-guided high intensityfocused ultrasound treatments, which have limited visualization during the course of the treatment and lack of knowledge on the temperature reached at the focus of the energy delivery. MRgFUS uses real-time thermal images to provide accurate tissue thermal responses as well as real-time anatomical images. The former allows the physician operating the MRgFUS system to perform the necessary protocol adjustments in case the appropriate temperature levels are not reached. The latter provides the physician with an indication of whether the patient or an internal organ has shifted in comparison with the planned location Conservative surgeries such as local excision of adenomyosis lesions are difficult because of the ill-defined boundary between the endometrium and myometrium. Hysteroscopic endometrial resection is a minimally invasive option that can be used in a minority of patients who are seen with minor symptoms of menorrhagia (3). Uterine artery embolization has gained acceptance as an effective alternative to surgical treatment with control of symptoms (4–6). The levonorgestrelreleasing intrauterine system appears to be an effective method in alleviating dysmenorrhea associated with adenomyosis (7). Conservative medical management including danazol, GnRH analogues, nonsteroidal anti- inflammatory drugs, and oral contraceptives can provide temporary symptomatic relief (8). As a result, a new noninvasive method for the treatment of patients with adenomyosis would be of great value. High-intensity focused ultrasound (HIFU) is a powerful tissueablation technique that has been used to treat a variety of tumors of the prostate, breast, and liver, with use of either ultrasound (US) or magnetic resonance imaging (MRI) guidance (9–12). It is a noninvasive thermoablative technique that uses an external US energy source to induce a thermal ablation of tissue deep under the intact skin based on its ability to concentrate US waves precisely (12). High-intensity focused US has been used for the treatment of uterine fibroids, showing a symptom reduction İn women with symptomatic uterine leiomyomas and an excellent safety profile (13–15), with obvious necrosis histopathologically (16). High-intensity focused US–induced thermal ablation also results in typical characteristics of coagulative necrosis, and the margin between the treated and untreated regions is well defined (17). Although several publications (18–21) indicate that focused US ablation is safe and effective in the treatment of adenomyosis, (A) Before treatment. (B) Three months after treatment, showing a nonperfused region over 50% of lesion. (

20 For the extent of coagulative necrosis assessed by enhanced MRI, 60 patients (87.0%) who had a nonperfused region had their treatment area assessed. Among the patients, there were a nonperfused region over 50% of lesion in 47 patients (68.1%) and a nonperfused region below 50% of lesion in 13 patients (18.9%), and there were 9 (13.0%) without a nonperfused region. Examples of the MRI are shown in Figure 1. There was statistical significance between the extent of nonperfused region and the clinical outcomes (P¼.004; see Table 1). The results of this study show that US-guided HIFU ablation appears to be a safe intervention for the treatment of adenomyosis. In addition, this method is well tolerated by patients. During an average of 24 months of follow-up (range: 18–36 months), it was observed that the relief from symptoms was maintained. Moreover, our results show that the extent of nonperfused regions that exceeded 50% of lesions resulted in improved clinical efficacy, and, as a general rule, the larger the extent of coagulative necrosis, the better the clinical efficacy of the treatment. Dismenore ve menoraji için ! Successful use of magnetic resonance–guided focused ultrasound surgery to relieve symptoms in a patient with symptomatic focal adenomyosis For women who wish to preserve their uterus, hormonal medications such as antiprostaglandins, combined estrogen–progestin, progestins, danazol, and gonadotropin-releasing hormone (GnRH) analogs may be used to relieve adenomyosis symptoms. However, these medications offer only temporary alleviation of symptoms and also are associated with side effects Magnetic resonance–guided focused ultrasound surgery (MRgFUS) is a noninvasive treatment for soft tissue tumors. The procedure is approved for the treatment of uterine fibroids, The MRI scan showed multiple, small, highsignal intensity spots, which likely resulted from islands of ectopic endometrial tissue and cystic dilatation of glands. In addition, the tumor had poorly demarcated margins, which suggested against a degenerated cystic uterine fibroid (

21 Konservatif cerrahi Komplet eksizyon Sitoredüktif cerrahi
Adenomyomektomi Kistektomi Sitoredüktif cerrahi Noneksizyonel teknikler Nevertheless, conservative surgery has not become the standard treatment for adenomyosis. This is mainly because adenomyotic tissue invades the uterine muscle layer in a way that make the borders of the lesion unclear, so complete excision of the affected area remains inaccurate (11). Moreover, the excision of adenomyotic tissue is always accompanied by excision of myometrium, so it is partly destructive for the uterine wall: the advantages of removing an affected area must be balanced against the disadvantages of leaving a possibly defective uterine wall operative options include nonstandardizedvcytoreductive approaches Cytoreductive surgery/partial adenomyomectomy. Used in cases of diffuse adenomyosis, including the partial removal of the clinically recognizable non-microscopic lesions because complete removal of the lesion would lead to the concomitant excision of critical amount of healthy myometrium, which could lead to ‘‘functional’’ hysterectomy (13, 22). During the last decades, there is an increasing trend of getting pregnant at a later age. Adenomyosis, a disease mostly diagnosed between 30 and 45 years of age, increasingly complicates the fertility potential of women in this age group Laparoscopic uterine artery occlusion. 2. Laparoscopic nonexcisional techniques. These techniques include laparoscopic electrocoagulation of the myometrium (22, 23, 34) and laparoscopic uterine artery ligation (24). 3. Hysteroscopic nonexcisional techniques. These techniques include operative hysteroscopy (35), rollerball endometrial ablation (36), transcervical resection of the endometrium (37, 38), and endomyometrial resection (22). 4. Other techniques. These techniques include ablation of focal adenomyosis with high frequency ultrasound (HIFU) (39), alcohol instillation under ultrasound guidance for the treatment of cystic adenomyosis (40), radiofrequency ablation of focal adenomyosis (41), microwave endometrial ablation (42), and balloon thermoablation (43) for diffuse adenomyosis. The pregnancy rate ranges from 46.9% (partial adenomyomectomy) to 60.5% (complete adenomyomectomy). eir disadvantages include partial eYcacy and compromised fertility due to incomplete excision, scarring and reduced uterine volume. Laparoscopic cytoreductive surgery can be an alternative treatment to the use of hypoestrogenic agents or hysterectomy in women with localized adenomyosis, especially for those who want to maintain their fertility and achieve successful pregnancies. To date, conservative surgical intervention hardly plays a role in the management of infertile patients with adenomyosis, partly because it is difficult to completely clear adenomyotic lesions without removal of the uterus, and partly because parity appears to correlate with adenomyosis The biggest challenge with cytoreductive surgery is excision of diffuse adenomyosis whilst avoiding intraoperative complications in the longterm sequelae such as reduced uterine capacity and scarring Wood [14] reported spontaneous rupture at 12 weeks following electrocoagulation, Wang et al. reported uterine rupture at 30 weeks following laparoscopic excision in a twin pregnancy [31]. Recently, a case of total uterine rupture at 28 weeks gestation requiring hysterectomy in a patient following an open adenomyomectomy was reported [32]. Pathologically, the cause of rupture was attributed to residual adenomyotic fragments within the uterine scar, which were susceptible to decidualization and weakening during pregnancy that women who conceiveafter surgical management of adenomyosis need very careful management throughout the entire pregnancy and a low threshold for diagnosing uterine rupture

22 In conclusion, the triple-flap method offers the following advantages
In conclusion, the triple-flap method offers the following advantages. First, it permits the excision of the affected tissues more widely and thoroughly than the conventional wedge resection. As a result, it appears to be extremely effective for the management of dysmenorrhoea and hypermenorrhoea. Secondly, the massive tissue defects created by the wide excision of the lesion can be reconstructed into a uterine wall of adequate thickness by the three layers of myometrium in the reconstructed wall, making the reconstructed uterus more capable of sustaining a normal pregnancy without the risk of uterine rupture. However, this approach is associated with a frequent recurrence of adenomyosis and spontaneous uterine rupture in pregnancy (Wada et al., 2006). Effective treatment requires more radical resection of the affected tissues. However, this may result in creating large defects in the uterine wall, making the reconstructed uterus incapable of sustaining a normal pregnancy. Therefore, the usual treatment for women with severe or disabling adenomyosis is hysterectomy. Yet many of these women do not want a hysterectomy and wish to carry a child. The surgical procedure consists of radical excision of adenomyosis (leaving a 1 cm margin of tissue above the endometrium and a 1 cm margin of tissue below the serosal surface), with subsequent triple-flap reconstruction of the uterus Osada et al, RBM online, 2011

23 Dismenorenin azalması
It seems that the excision of the bulk of adenomyosis controls the pain even if some amount of residual lesion has been left, as happens in cases of cytoreductive surgery. However, all the series included are studies where specially designed cytoreductive techniques were applied, such as the triple flap Osada technique (20), and these results could not be generalized across all the techniques used for the conservative surgery (such as the ‘‘wedge’’ resection technique, represented in this review by only a few case reports). Grimbizis et al FS 2014

24 Menorajinin Kontrolü Grimbizis et al FS 2014
In terms of menorrhagia control, the results differed after partial excision of adenomyosis (50.00% reduction) and complete excision of adenomyosis (68.79% reduction). With nonexcisional techniques, the control of menorrhagia appears to be better compared with the partial excision techniques, and to be comparable to that of the complete excision techniques (73.7%). Nonexcisional techniques is an heterogeneous group of operations including many cases of hysteroscopic ablation. In these cases, the control of bleeding is achieved through the destruction/excision of endometrium, resulting in loss of the fertility of the patient; in addition, in the group of nonexcisional techniques, control of symptoms is achieved indirectly and without treatment of the primary disease. Furthermore, it seems that, especially after partial excision of adenomyosis, the residual lesion adjacent to the endometrium continues to cause bleeding symptoms. This is an implication for clinical practice: in cases of diffuse adenomyosis with menorrhagia, cytoreductive partial excision of the lesion is less effective compared with complete excision techniques or nonexcisional techniques where fertility may be lost. Grimbizis et al FS 2014

25 Konsepsiyon oranları Grimbizis et al FS 2014
On the other hand, uterussparing surgery for adenomyosis involves techniques that modify the anatomy of the uterus (i.e., pelvic adhesions, uterine deformities, intrauterine adhesions, or reduced uterine capacity). These deformities may contribute to a declined postoperative pregnancy rate (13). Nevertheless, not only was fertility finally preserved, but any subfertility related to adenomyosis appears largely to be treated after cytoreductive surgery, considering that the crude delivery rate appears to be higher than 70%. In view of the fact that pregnancy rates after surgical treatment of fibroids appear to be 50%, the postoperative fertility outcome after excision of adenomyosis should be considered satisfactory It has been reported that ART methods show increased pregnancy rates compared with natural cycles after an operative intervention for adenomyosis (30). Furthermore, there is a recognized risk of uterine rupture during pregnancy or labor after conservative surgery for adenomyosis Grimbizis et al FS 2014

26 Case1 33 yrs Infertility DOR Recurrent IVF failures
Severe dysmenorrhea Severe menorrhagia

27 Wound apposition Dificult to achieve as the loss of circumference of myometriumwill increase tension in the strecthed myometri when it is opposed to fill the gap. Additionally, initial experience with simple excision of adenomyotic lesions and covering or simply closing the myometrium was reported to be disappointing because this group of patients had quick recurrences and soon needed hysterectomy removal of healthy myometrium happens inevitably during excision of the lesion

28 Postop 12 mo

29 Extent of removal Incomplete excision still cure or symptom reduction One factor that favour attemps at excision of localized aeas of adenomyosis is the possibilty of reduction or cure of sypmtps even when excision is incomplete.symptom relief lasts for 3 years sometimes.

30 Case 2 43 yrs Recurrent IVF failures Severe dysmenorrhea
Heavy menorrhagia Adenomyotic area ~ 6 cm thick on posterior surface

31 the difference between the adenomyotic nodule and healthy muscles could be distinguished by the difference in extensibility. Adenomyosis tissues are less elastic than the normal uterine muscles because of fibrotic changes. However, because the border is unclear, we made incision to the healthy uterine muscles just adjacent to the adenomyosis foci. In this way, we remove the adenomyosis foci en bloc as completely as possible. After removal of the adenomyosis foci, the defected spaces were carefully repaired with continuous stitches of 2-0 synthetic absorbable sutures to close the residual myometrium. When the tissue is very firm the scalpel may be preferable, providing more effective and rapid excision. The margin of the adenomyosis may be determined by change in appearance, vascularity or consistency; finger palpation may be an advantage. Attention is taken to not leave any uterine defect that could increase the risk of hematoma

32 Postop 10 d Postop 2 mo Postop 12 mo

33 Our experince of conservative laparoscopic surgery in adenomyosis
case age dysmenorrhea menorrhagia infertility symptomatic remission at 12 mo sonographic remission pregnancy 1 33 +++ ++ + complete partial - 2 43 + (IVF) 3 39 4 32

34 Adenomyozise bağlı subfertilitede kim uterus koruyucu cerrahiden fayda görür ?
is thought to be found most likely during the fourth and fifth decades of life and after childbearing activity. However, with the trend of delayed childbearing, adenomyosis has come to be diagnosed more frequently in fertility clinics (2, 3). This is also thought to be caused by the recent development of diagnostic tools such as high-resolution transvaginal sonography and magnetic resonance imaging (MRI). With the aid of these diagnostic tools, uterine adenomyosis is becoming a more common disease among women with childbearing desire and showing more diversity (4–9). Recently, the correlation between adenomyosis and endometriosis has gradually been revealed (4–9). We often encounter uterine adenomyosis without junctional zone (JZ) changes. This atypical adenomyosis often coexists with severe endometriosis and is localized at the outer myometrium without aberrations of the subendometrial myometrium This study demonstrated the advantage of fertility outcomes in younger women after uterus-sparing surgery for the uterine adenomyosis. This type of surgery could be a beneficial treatment for women who have experienced IVF treatment failures, especially at ages of %39 years

35 The clinical pregnancy rate was totally 31. 4% (32/102)
The clinical pregnancy rate was totally 31.4% (32/102). When the women were divided into %39 and R40 years, clinical pregnancy rates were 41.3% and 3.7%, respectively. In the older group, 5/6 of the pregnancies ended in miscarriages. we analyzed fertility outcomes on women who had a history of IVF failures. In the younger group, 60.8% of the women succeeded in postoperative clinical pregnancy. In contrast, the clinical pregnancy rate of the older group was 7.1%. Most of the women had successful pregnancies with the use of IVF ‘‘History of preoperative IVF treatments’’ was extracted as a factor relating to clinical pregnancy inmultivariable regression analysis. When we examine the details, inthe younger group (%39 years) a total of 60.8% of women with a history of preoperative IVF failures showed successful postoperative pregnancy. In contrast, the older age group (R40 years) resulted in only a 7.1% clinical pregnancy rate In earlier reports, successful pregnancy rates following IVF-ET of women with adenomyosis were reported to be 11%–35%.... Our study included 37 women who were recommended to have surgical intervention because of repeated IVF failures. For these women we performed an adenomyomectomy, and roughly 60% of those in the younger group succeeded in postoperative IVF treatments. This result suggests a possible beneficial effect of adenomyomectomy on patients who experience IVF failures, especially at ages %39 years

36 Uterine rupture was not found in this series
Uterine rupture was not found in this series. There were two cases of placenta accreta; they underwent postpartum hysterectomies, without severe maternal or fetal complications. Two cases of threatened preterm birth were managed by tocolytic treatment and underwent elective cesarean sections at 35 and 36 weeks gestational age Another important subject that should be taken account in this type of surgery is uterine rupture during pregnancy or labor. In this study, we did not experience a uterine rupture. However, recently we experienced a case of uterine rupture after adenomyomectomy (this case was not in the present study period), and that case also was far advanced. We consider that the size of adenomyosis is the most important factor linked to uterine ruptures With the use of univariable analysis, there was a significant difference in r-AFS scores between the groups. The total clinical pregnancy rate in our cases was 31.4% (32/102). Live birth rates following conservative surgery for uterine adenomyosis were reported to be 32%–36%

37 In the functional aspect, uterine myometrium could be divided into subendometrial myometrium (JZ) and outer myometrium, where the former is involved in preparation of the endometrium for implantation and uterine peristalsis: sperm transport and hemostasis during menstruation (26–31). Based on these findings, we categorized the present cases into two groups according to the functional aspect: the presence or not of JZ changes. Moreover, we added a topologic categorization: anterior and posterior wall involvements. As a result, only the topologic factor of posterior wall involvement of adenomyosis was extracted as a negative factor relating to clinical pregnancy (odds ratio 0.18). How should we interpret this result? In our previous study, we demonstrated that extrinsic adenomyosis has a characteristic that it is found mostly on the posterior wall, coexisting with pelvic endometriosis (9). Again, with the use of univariable analysis, r-AFS scores of the unsuccessful group were significantly higher than those of the successful group, which means that there was a tendency of women in the unsuccessful group to have more severe forms of endometriosis. On the other hand, we can nterpret this result from another viewpoint. In the unsuccessful group, 19/69 (27.5%) of the women had adenomyosis at both anterior and posterior wall; in the successful grouponly one women was affected at both anterior and posterior wall. From these details, the severity of endometriosis and extent of adenomyosis could be considered to be negative factors relating to clinical pregnancy.

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