Pathogenesis of Adenomyosis: An Update On Molecular Mechanisms

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Q2 Review
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3 bs_bs_query Pathogenesis of adenomyosis: an update on molecular

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Q1 Silvia Vannuccini a, Claudia Tosti a, Francisco Carmona b, S Joseph Huang c,d,
8 bs_bs_query Charles Chapron e,f,g, Sun-Wei Guo h,i, Felice Petraglia a,*
a
9 bs_bs_query Obstetrics and Gynecology, Department of Molecular and Developmental Medicine University of Siena, Siena, Italy
b
10 bs_bs_query Clinical Institute of Gynecology, Obstetrics, and Neonatology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain Group of
11 bs_bs_query Endocrinology, Gynecology and Human Reproduction, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
c
12 bs_bs_query Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
d
13 bs_bs_query Department of Obstetrics and Gynecology, Morsasni College of Medicine, University of South Florida, Tampa, FL, USA
e
14 bs_bs_query Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Paris
15 bs_bs_query Centre, Centre Hospitalier Universitaire Cochin, Department of Gynaecology Obstetrics II and Reproductive Medicine, Paris, France
f
16 bs_bs_query Institut Cochin, INSERM U1016, Laboratoire d’Immunologie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
g
17 bs_bs_query Département de Génetique, Développement et Cancer, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
h
18 bs_bs_query Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China
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Q3 i Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
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22 bs_bs_query Felice Petraglia is Professor and Chairman of Obstetrics and Gynecology. He is Fellow ad Eundem of the Royal
23 bs_bs_query College of Obstetricians and Gynecologists (RCOG). He was President of the Society for Gynecologic Investiga-
24 bs_bs_query tion (SGI). He is Editor-in-Chief of Human Reproduction Update and Section Head in Reproductive Endocrinology
25 bs_bs_query of Faculty 1000 Medicine.
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27 bs_bs_query KEY MESSAGE

28 bs_bs_query Sex steroid receptors, proliferation and fibrosis, inflammatory mediators and neuroangiogenesis are key patho-
29 bs_bs_query genetic mediators of adenomyosis-related pain, abnormal uterine bleeding and infertility.
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31 bs_bs_query A B S T R A C T
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33 bs_bs_query Adenomyosis is a uterine disorder becoming more commonly diagnosed in women of reproductive age because of diagnostic imaging advancements.
34 bs_bs_query The new epidemiological scenario and the clinical evidence of pelvic pain, abnormal uterine bleeding and infertility are changing the classic perspec-
35 bs_bs_query tive of adenomyosis as a premenopausal disease. In the last decade, the evaluation of multiple molecular mediators has improved our knowledge of
36 bs_bs_query pathogenic mechanisms of adenomyosis, supporting that this is an independent disease from endometriosis. Although they share common genetic
37 bs_bs_query mutations and epigenetic changes in sex steroid hormone receptors and similar inflammatory mediators, an increasing number of recent studies have
38 bs_bs_query shown pathogenic pathways specific for adenomyosis. A PubMed search up to October 2016 summarizes the key mediators of pain, abnormal uterine
39 bs_bs_query bleeding and infertility in adenomyosis, including sex steroid hormone receptors, inflammatory molecules, extracellular matrix enzymes, growth factors
40 bs_bs_query and neuroangiogenic factors.
41 bs_bs_query © 2017 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
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43 bs_bs_query * Corresponding author.

44 bs_bs_query E-mail address: felice.petraglia@unisi.it (F Petraglia).
45 bs_bs_query http://dx.doi.org/10.1016/j.rbmo.2017.06.016
46 bs_bs_query 1472-6483/© 2017 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Please cite this article in press as: Silvia Vannuccini, et al., Pathogenesis of adenomyosis: an update on molecular mechanisms, Reproductive BioMedicine Online (2017),
doi: 10.1016/j.rbmo.2017.06.016
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2 REPRODUCTIVE BIOMEDICINE ONLINE ■■ (2017) ■■–■■
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myometrium through an altered or absent junctional zone (JZ) 108 bs_bs_query
48 bs_bs_query Introduction (Bergeron et al., 2006; Parrott et al., 2001). Thus, the endometrium 109 bs_bs_query
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can slip through bundles of weak smooth muscle fibres that have loos- 110 bs_bs_query
50 bs_bs_query Adenomyosis is defined as the presence of ectopic endometrial glands ened their tissue cohesion. Dysregulation of genes and pathways in 111 bs_bs_query
51 bs_bs_query and stroma surrounded by hyperplastic smooth muscle within the myo- the eutopic endometrium may predispose to ectopic migration and 112 bs_bs_query
52 bs_bs_query metrium. It is a uterine disorder clinically presented with pelvic pain, implantation. The analysis of the global transcriptome of eutopic en- 113 bs_bs_query
53 bs_bs_query abnormal uterine bleeding (AUB) and infertility. Dysmenorrhoea and dometrial cells from women with clinically significant adenomyosis 114 bs_bs_query
54 bs_bs_query dyspareunia are the most common symptoms; however, the clinical revealed 140 up-regulated and 884 down-regulated genes, com- 115 bs_bs_query
55 bs_bs_query presentation of adenomyosis is often mixed and occasionally it may pared with controls. Genes involved in regulation of apoptosis, steroid 116 bs_bs_query
56 bs_bs_query even be asymptomatic (Farquhar and Brosens, 2006). Rokitansky first hormone responsiveness and extracellular matrix remodelling as well 117 bs_bs_query
57 bs_bs_query recognized adenomyosis in 1860 but the term was first used by Frankl as microRNAs of unknown significance were found to be highly dif- 118 bs_bs_query
58 bs_bs_query in 1925 (Benagiano et al., 2012; Leyendecker et al., 2006). Before the ferentially expressed. Affected canonical pathways included eukaryotic 119 bs_bs_query
59 bs_bs_query advancement of imaging techniques such as transvaginal ultra- initiation factor 2 (eIF2) signalling, oxidative phosphorylation, mito- 120 bs_bs_query
60 bs_bs_query sound scan (TVUS) and magnetic resonance imaging (MRI), chondrial dysfunction, oestrogen receptor (ER) signalling, and 121 bs_bs_query
61 bs_bs_query adenomyosis could only be diagnosed by histology after hysterec- mammalian target of rapamycin (mTOR) signalling (Herndon et al., 122 bs_bs_query
62 bs_bs_query tomy. Two different pathological aspects of adenomyosis are described: 2016). These aberrant pathways may predispose toward the devel- 123 bs_bs_query
63 bs_bs_query diffuse and focal forms (when a defined nodule is found, the term ad- opment, migration and survival of ectopic endometrial implants beyond 124 bs_bs_query
64 bs_bs_query enomyoma is also used). Adenomyosis and endometriosis share a the myometrial interface. However, further studies are needed to elu- 125 bs_bs_query
65 bs_bs_query number of features and it was found that, at least in some sub- cidate the biological significance of these aberrations, especially in 126 bs_bs_query
66 bs_bs_query groups, the two conditions often coexist (Lazzeri et al., 2014; Li et al., the early developmental stage of the disease. 127 bs_bs_query
67 bs_bs_query 2014), so much so that for a long time adenomyosis had been termed
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68 bs_bs_query endometriosis interna. Nevertheless, they are considered as two dis-

69 bs_bs_query tinct entities because many differences have been observed in Mechanism of TIAR 129 bs_bs_query
70 bs_bs_query pathogenesis, risk factors and clinical presentation (Benagiano et al., The phenomenon of endometrial invasion may happen in a predis- 130 bs_bs_query
71 bs_bs_query 2014). Despite all these differences, the two conditions have many posed myometrium or in a traumatized endometrial–myometrial 131 bs_bs_query
72 bs_bs_query similarities in definition, symptomology and molecular aberrations interface (Benagiano et al., 2012). Uterine auto-traumatization and 132 bs_bs_query
73 bs_bs_query (Li et al., 2013). Above all, adenomyosis and endometriosis share the initiation of the mechanism of TIAR have been considered as the 133 bs_bs_query
74 bs_bs_query same commonality of experiencing cyclic bleeding (Liu et al., 2016; primary events in the disease process. A condition of chronic prolif- 134 bs_bs_query
75 bs_bs_query Shen et al., 2016). eration and inflammation induced at the level of the archimetra by 135 bs_bs_query
76 bs_bs_query The pathogenic mechanisms of adenomyosis development are still chronic uterine auto-traumatization supports one of the theories for 136 bs_bs_query
77 bs_bs_query debatable; however, sex steroid hormone aberrations, inflamma- adenomyosis pathophysiology (Leyendecker et al., 2015). Accord- 137 bs_bs_query
78 bs_bs_query tion, altered cell proliferation and neuroangiogenesis are likely key ingly, the TIAR mechanism, in response to increased intrauterine 138 bs_bs_query
79 bs_bs_query pathogenic mechanisms of pain, AUB and infertility in adenomyosis. pressure, may promote the migration of fragments of basal endo- 139 bs_bs_query
80 bs_bs_query In this review, we summarize all the available evidence on specific metrium into the myometrium. In a recent study a new software was 140 bs_bs_query
81 bs_bs_query pathways and mediators involved in the pathogenesis of adenomyo- used to develop a conceptual two-dimensional model of the uterine 141 bs_bs_query
82 bs_bs_query sis, explaining the clinical presentation of the disease. wall subjected to a variety of intrauterine sinusoidal pressure waves 142 bs_bs_query
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with varying frequencies. It was noted that a decrease in wave- 143 bs_bs_query
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Q4 Sources length and an increase in frequency of the subjected pressure wave 144 bs_bs_query
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led to high levels of stress near the inner uterine cavity. During men- 145 bs_bs_query
86 bs_bs_query A PubMed search of the literature from 1950 to October 2016 was per- struation, the highest stress was observed at the endometrial– 146 bs_bs_query
87 bs_bs_query formed in order to summarize all evidence on pathogenic mechanisms myometrial interface. Hence, high stress caused by increased uterine 147 bs_bs_query
88 bs_bs_query of adenomyosis development and clinical presentation. All perti- activity may lead to tissue lesions and detachment of endometrial cells 148 bs_bs_query
89 bs_bs_query nent articles were examined and their reference lists were reviewed (Shaked et al., 2015). 149 bs_bs_query
90 bs_bs_query in order to identify other studies for potential inclusion. The litera- Chronic peristaltic myometrial contractions induce microtrauma 150 bs_bs_query
91 bs_bs_query ture search included the following terms: ‘adenomyosis’, to the JZ, causing a vicious cycle in which local oestrogen produc- 151 bs_bs_query
92 bs_bs_query ‘adenomyoma’, ‘pathogenesis’, ‘pain’, ‘abnormal uterine bleeding’, ‘in- tion, COX-2 mediated (Chen et al., 2010a), promotes uterine peristalsis 152 bs_bs_query
93 bs_bs_query fertility’, ‘sex steroid hormones’, ‘sex steroid hormone receptors’, and further auto-traumatization (Gargett et al., 2016; Leyendecker 153 bs_bs_query
94 bs_bs_query ‘inflammation’, ‘neoangiogenesis’, ‘growth factors’, ‘extracellular et al., 2009). 154 bs_bs_query
95 bs_bs_query matrix (ECM)’, ‘fibrosis’, ‘proliferation’ and ‘neurogenic factors’. Only On the basis of small-diameter nerve fibre proliferation ob- 155 bs_bs_query
96 bs_bs_query peer-reviewed, English-language journal articles were included. served in the myometrium of patients with chronic pelvic pain (Quinn 156 bs_bs_query
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and Kirk, 2002), Quinn postulated that nerve injury (denervation) in 157
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the uterus and/or uterosacral ligaments may lead to endometriosis 158 bs_bs_query
100 bs_bs_query Despite the prevalence of the disease, its precise aetiology and phys- (Quinn, 2004; Quinn and Kirk, 2004; Quinn, 2011) and also to adeno- 159 bs_bs_query
101 bs_bs_query iopathology remain in part unknown. Some hypotheses have been myosis (Quinn, 2007). Nerve injury might be due to either difficult 160 bs_bs_query
102 bs_bs_query developed, suggesting the role played by the endometrium, the mecha- intrapartum episodes or persistent straining to achieve defecation. 161 bs_bs_query
103 bs_bs_query nism of tissue injury and repair (TIAR) and stem cell theory. The resulting re-innervation of the uterine isthmus may be the primary 162 bs_bs_query
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source of many pain symptoms in adenomyosis (Quinn, 2007). 163 bs_bs_query
105 bs_bs_query Invasion from the endometrium While these hypotheses and theories are intuitive and attractive, 164 bs_bs_query
106 bs_bs_query According to the current theory, adenomyosis develops through down- the biggest challenge is to make them falsifiable, i.e. able to be tested 165 bs_bs_query
107 bs_bs_query growth and invagination of the endometrium basalis into the with a well-designed experiment. In addition, these hypotheses and 166 bs_bs_query
doi: 10.1016/j.rbmo.2017.06.016
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167 bs_bs_query theories need to, by default, explain all existing data and should also in the adenomyosis foci throughout the menstrual cycle (Kitawaki, 210 bs_bs_query
168 bs_bs_query predict new phenomena. 2006). Local hyperestrogenism leads to increased peristalsis of the 211 bs_bs_query
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subendometrial myometrium, imposing supraphysiological mechani- 212 bs_bs_query
170 bs_bs_query Stem cell theory cal strain on the cells near the fundo-cornual raphe. This state 213 bs_bs_query
171 bs_bs_query Another theory proposes that adenomyosis, like endometriosis, might activates the TIAR system focally with further local production of 214 bs_bs_query
172 bs_bs_query develop through metaplasia from de novo ectopic intramyometrial en- oestradiol. 215 bs_bs_query
173 bs_bs_query dometrial tissue (Hufnagel et al., 2015). The endometrium is a Sustained hyperperistaltic activity and chronic injury, prolifera- 216 bs_bs_query
174 bs_bs_query pluripotent tissue, which shares a common embryological origin from tion and inflammation delay the healing process and result in increased 217 bs_bs_query
175 bs_bs_query the müllerian ducts with subjacent myometrium. It is composed of numbers of foci. Hence, local areas of the basal endometrium, because 218 bs_bs_query
176 bs_bs_query glands and stroma, with cytokeratin filament-containing epithelial of accumulation or expansion of such sites, start functioning as an 219 bs_bs_query
177 bs_bs_query tissue and vimentin-containing mesenchymal tissue, as in adeno- endocrine gland that produces oestradiol. The hyperestrogenism is 220 bs_bs_query
178 bs_bs_query myosis (Moll et al., 1983). Progenitor cells deposited in the peritoneal suggested to result from the activation of aromatase and sulphatase. 221 bs_bs_query
179 bs_bs_query cavity by retrograde menstruation can possibly lead to the focal uterine This finding is reflected by the increased levels of oestradiol in men- 222 bs_bs_query
180 bs_bs_query adenomyosis. Alternatively, adenomyosis can differentiate from strual blood, but not in peripheral blood of women with adenomyosis 223 bs_bs_query
181 bs_bs_query multipotent stem cells originated from bone marrow and other (Rižner, 2016). A vicious cycle is generated by a paracrine effect re- 224 bs_bs_query
182 bs_bs_query sources. sulting from focal oestrogen production, presumably mediated by 225 bs_bs_query
183 bs_bs_query More recently, it has been demonstrated that adult stem cells are endometrial oxytocin and its receptor, which increases uterine peri- 226 bs_bs_query
184 bs_bs_query activated by tissue injury, promoting ectopic endometrial implants stalsis. Furthermore, the altered regulation of 17ß-hydroxysteroid 227 bs_bs_query
185 bs_bs_query through endometrial stem/progenitor cell niche disruption (Gargett, dehydrogenase type 2 (17β-HSD2) in the eutopic endometrium of 228 bs_bs_query
186 bs_bs_query 2007). However, more research is required to establish a role for en- women with adenomyosis causes a decreased local oestrogen me- 229 bs_bs_query
187 bs_bs_query dometrial stem/progenitor cells in the initiation and progression of tabolism (Kitawaki et al., 2000) (Figure 2). The evidence that 230 bs_bs_query
188 bs_bs_query adenomyosis (Gargett et al., 2016). adenomyosis is an oestrogen-related process is also supported by 231 bs_bs_query
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the observation that postmenopausal women with breast cancer 232 bs_bs_query
treated with tamoxifen have a higher rate of adenomyosis than those 233
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untreated (Cohen et al., 1998). Therefore, prolonged tamoxifen therapy, 234 bs_bs_query
192 bs_bs_query The main mechanisms involved in adenomyosis include sex steroid as a result of its oestrogenic effects, may promote the development 235 bs_bs_query
193 bs_bs_query hormone aberrations, proliferation and fibrosis, inflammation and of adenomyosis or its persistency in postmenopause (McCluggage 236 bs_bs_query
194 bs_bs_query neuroangiogenesis (Figure 1), which in part explain the clinical symp- et al., 2000). 237 bs_bs_query
195 bs_bs_query toms of pain, AUB and infertility. Moreover, the increased expression of ER induces a down- 238 bs_bs_query
regulation of progesterone receptors, a loss of their action and finally 239

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progesterone resistance (Jichan et al., 2010; Kitawaki et al., 2000). 240 bs_bs_query
197 bs_bs_query Sex steroid hormone aberrations

Ectopic and eutopic endometrium from women with adenomyosis show 241 bs_bs_query
198 bs_bs_query Steroid hormones are involved in the pathogenesis of adenomyosis.

a reduction in progesterone receptor isoform B (PR-B) and IκB-α im- 242 bs_bs_query
199 bs_bs_query The uterine dysfunction may be the result of local hyperestrogen-
munoreactivity, and an increase in nuclear p65, p50 and p52 expression. 243 bs_bs_query
200 bs_bs_query ism with normal peripheral oestradiol levels (Urabe et al., 1989). This
In addition, nuclear p65 immunoreactivity is correlated with heavy men- 244 bs_bs_query
201 bs_bs_query hormonal status represents the ‘primum movens’ of a chain of key
strual bleeding, while the severity of dysmenorrhoea is significantly 245 bs_bs_query
202 bs_bs_query events. Indeed, polymorphisms of the ER-α gene causing increased
associated with both decreased PR-B and increased nuclear p65 im- 246 bs_bs_query
203 bs_bs_query receptor activity are associated with a risk of adenomyosis (Oehler
munoreactivity in ectopic endometrium of women with adenomyosis 247 bs_bs_query
204 bs_bs_query et al., 2004). The invagination process and overall ‘spreading’ of ad-
(Nie et al., 2009) (Figure 2). 248 bs_bs_query
205 bs_bs_query enomyosis into the myometrium are suggested to be promoted by the
The immunoreactivity to deoxyribonucleic acid methyltransferases 249 bs_bs_query
206 bs_bs_query non-cyclic and anti-apoptotic activity of the basalis, which is associ-
(DNMTs) in adenomyosis differs significantly from that in normal en- 250 bs_bs_query
207 bs_bs_query ated with increased oestrogen receptor (ER) and Bcl-2 gene expression
dometrium, suggesting that adenomyosis may be a disease caused 251 bs_bs_query
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209 bs_bs_query Figure 1 – Pathogenetic mechanisms of adenomyosis. Figure 2 – Pathogenic mediators in adenomyosis. 253 bs_bs_query
doi: 10.1016/j.rbmo.2017.06.016
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254 bs_bs_query by epigenetic dysregulation of genes. DNMT1 and DNMT3B expres- smooth muscle cells (uSMCs) of women with adenomyosis (Streuli 313 bs_bs_query
255 bs_bs_query sion has been shown to be higher in ectopic endometrium, while et al., 2015) (Figure 2). 314 bs_bs_query
256 bs_bs_query DNMT3A levels are reduced in both eutopic and ectopic endome- According to the invagination theory, adenomyosis results from 315 bs_bs_query
257 bs_bs_query trium. DNMT1 levels in eutopic endometrium are positively associated the increased invasiveness of the endometrial cells. It has been re- 316 bs_bs_query
258 bs_bs_query with heavier menses. The correlation between DNMT3B and the se- ported that oestrogen-induced epithelial-to-mesenchymal transition 317 bs_bs_query
259 bs_bs_query verity of dysmenorrhoea suggests a role for DNMTs in adenomyosis- (EMT), a developmental programme exploited by cancer cells for their 318 bs_bs_query
260 bs_bs_query induced dysmenorrhoea (Liu and Guo, 2012). Furthermore, the invasive and metastatic capacity, is crucial to the pathogenesis of ad- 319 bs_bs_query
261 bs_bs_query expression profile of long non-coding RNA (lncRNA) – a key regula- enomyosis (Chen et al., 2010b; Khan et al., 2014; Oh et al., 2013). EMT 320 bs_bs_query
262 bs_bs_query tor of gene expression – is altered in eutopic endometrium of women is characterized by loss of E-cadherin and apical–basal cell polar- 321 bs_bs_query
263 bs_bs_query with adenomyosis (Jiang et al., 2016a). In addition, studies on ex- ity, increased expression of mesenchymal markers, including 322 bs_bs_query
264 bs_bs_query pression and localization of class I histone deacetylases (HDACs) have fibronectin, N-cadherin and vimentin. Hence, cells acquire migra- 323 bs_bs_query
265 bs_bs_query demonstrated that, compared with the normal endometrium, HDAC1 tion and invasion abilities (Polyak and Weinberg, 2009). Recent studies 324 bs_bs_query
266 bs_bs_query and HDAC3 expression was higher in both eutopic and ectopic en- have shown that focal adhesion kinase (FAK) is involved in EMT regu- 325 bs_bs_query
267 bs_bs_query dometria of women with adenomyosis. Similarly, HDAC2 expression lation (Serrels et al., 2011). The expression of FAK was shown to be 326 bs_bs_query
268 bs_bs_query in the eutopic endometrium was found to be associated with the se- higher in the eutopic endometrium of women with adenomyosis com- 327 bs_bs_query
269 bs_bs_query verity of dysmenorrhoea. These findings suggest the potential pared with controls and FAK levels are positively correlated with 328 bs_bs_query
270 bs_bs_query involvement of HDACs in the pathogenesis of adenomyosis (Liu and dysmenorrhoea and pelvic pain (Mu et al., 2015a). In adenomyosis the 329 bs_bs_query
271 bs_bs_query Guo, 2012; Liu et al., 2012). Consistent with these observations, the activation of FAK potentially promotes EMT and invasion and metas- 330 bs_bs_query
272 bs_bs_query promoter of PR-B has been reported to be methylated, rendering its tasis of endometrial cells by dysregulation of E-cadherin. It is possible 331 bs_bs_query
273 bs_bs_query silencing, which may be responsible for the well-known progestin re- that FAK is vital in transforming the eutopic endometrium of adeno- 332 bs_bs_query
274 bs_bs_query sistance in adenomyosis (Jichan et al., 2010). Encouragingly, the use myosis to be more resilient to surviving, adhering and growing in the 333 bs_bs_query
275 bs_bs_query of valproic acid, a histone deacetylase inhibitor, has been reported ectopic sites (Mu et al., 2015a). 334 bs_bs_query
276 bs_bs_query to be efficacious in treating refractory adenomyosis, alleviating dys- Among a group of dysregulated oestrogen-responsive proteins 335 bs_bs_query
277 bs_bs_query menorrhoea and reducing the uterus size (Liu and Guo, 2008; Liu et al., identified in adenomyosis, annexin A2 (ANXA2) was shown to be sig- 336 bs_bs_query
278 bs_bs_query
Q5 2010). Despite these promising results and the extensive in vitro and nificantly up-regulated in the ectopic rather than in the eutopic 337 bs_bs_query
279 bs_bs_query in vivo data favouring the use of HDAC inhibitors (Jichan et al., 2010; endometrium. Overexpression of ANXA2 is strongly correlated with 338 bs_bs_query
280 bs_bs_query Liu and Guo, 2011), so far there has been no independent validation markers of EMT and dysmenorrhoea severity in patients with adeno- 339 bs_bs_query
281 bs_bs_query and, more dishearteningly, no one has expressed interest in con- myosis. In an in vitro adenomyosis model, functional analysis indicates 340 bs_bs_query
282 bs_bs_query ducting clinical trials to evaluate the efficacy of valproic acid. Given that oestrogen could considerably up-regulate ANXA2 and induce EMT. 341 bs_bs_query
283 bs_bs_query that the patent for valproic acid expired a long time ago, the lack of Increased expression of ANXA2 promotes phenotypic mesenchymal- 342 bs_bs_query
284 bs_bs_query interest may simply reflect the lack of any financial incentive to pursue like cellular changes, with structural and functional alterations 343 bs_bs_query
285 bs_bs_query this drug. mediated by β-catenin/T-cell factor (Tcf) signalling and angiogen- 344 bs_bs_query
esis enhancement through the HIF-1α/VEGF-A pathway (Zhou et al., 345 bs_bs_query
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2012). 346 bs_bs_query
287 bs_bs_query Proliferation and fibrosis Similarly, loss of stromal caveolin (CAV1), a factor related to tumour 347 bs_bs_query
288 bs_bs_query An increased expression of growth factors (transforming growth factor progression, is involved in the pathogenesis of adenomyosis and 348 bs_bs_query
289 bs_bs_query β family, TGF-β) may play a role in the development of adenomyo- adenomyosis-related dysmenorrhoea. Immunochemical examina- 349 bs_bs_query
290 bs_bs_query sis. Myostatin, follistatin and activin A expression are increased in tion of stromal CAV1 showed a significantly lower expression in the 350 bs_bs_query
291 bs_bs_query adenomyotic nodules and may affect proliferation of endometrial ectopic endometrium of patients with adenomyosis than that of paired 351 bs_bs_query
292 bs_bs_query glands/stroma and of surrounding myometrial cells (Carrarelli et al., eutopic endometrium or normal controls. CAV1-depleted primary en- 352 bs_bs_query
293 bs_bs_query 2015). Myocytes are the main target of myostatin and their prolifera- dometrial stromal cells (ESCs) and endometrial epithelial cells (EECs) 353 bs_bs_query
294 bs_bs_query tive activity is modulated by these growth factors. Adenomyosis is demonstrated a significantly elevated proliferation rate, enhanced mi- 354 bs_bs_query
295 bs_bs_query characterized by hyperplasia of myometrial cells surrounding endo- gration and invasive capacity. Indeed, in women with more severe 355 bs_bs_query
296 bs_bs_query metrial stroma and glands that may be linked to the myostatin/ dysmenorrhoea a significantly lower stromal CAV1 expression in the 356 bs_bs_query
297 bs_bs_query follistatin overexpression. eutopic endometrium was observed, suggesting a negative correla- 357 bs_bs_query
298 bs_bs_query Activin-related proteins are also key regulators of tissue remod- tion with severity of pain symptoms in patients with adenomyosis. 358 bs_bs_query
299 bs_bs_query elling and repair. Up-regulation of these molecules in adenomyotic Conversely, a positive correlation between stromal RANTES expres- 359 bs_bs_query
300 bs_bs_query tissue may be related to myometrial response to ectopic endome- sion in the eutopic endometrium and severity of menstrual pain was 360 bs_bs_query
301 bs_bs_query trial cell invasion. There is strong evidence that myostatin, activin A reported in patients with adenomyosis (Zhao et al., 2013). 361 bs_bs_query
302 bs_bs_query and TGF-β normally inhibit muscle growth and promote muscle protein 362 bs_bs_query
303 bs_bs_query loss in disease states, acting as powerful catabolic stimuli. Binding Platelets 363 bs_bs_query
304 bs_bs_query of these TGF-β ligands to muscle cell surface receptors leads to One salient hallmark of adenomyotic lesions is cyclic bleeding, as in 364 bs_bs_query
305 bs_bs_query muscle proteolysis (Zhou et al., 2012), which can further support the endometriotic lesions (Brosens, 1997). Yet bleeding is a cardinal feature 365 bs_bs_query
306 bs_bs_query invagination theory in a ‘permissive’ myometrium. Such myome- of tissue injury. Once there is a tissue injury, tissue repair, an evo- 366 bs_bs_query
307 bs_bs_query trium is able to produce soluble factors (cytokines, chemokines, or lutionarily conserved mechanism in all organisms, will ensue. As such, 367 bs_bs_query
308 bs_bs_query other soluble molecules) that enhance the migration of stromal cells. platelets are involved in mammals when experiencing tissue injury. 368 bs_bs_query
309 bs_bs_query Furthermore, the mitogen-activated protein kinases/extracellular It has been shown recently that, indeed, platelets are highly aggre- 369 bs_bs_query
310 bs_bs_query signal-regulated kinases (MAPKs/ERKs) and phosphoinositide gated in endometriosis and seem to play important roles in the 370 bs_bs_query
311 bs_bs_query 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell- development of endometriosis (Ding et al., 2015). In fact, activated 371 bs_bs_query
312 bs_bs_query signalling pathways appear to be involved in proliferation of uterine platelets drive the EMT, fibroblast-to-myofibroblast transdifferentiation 372 bs_bs_query
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bs_bs_query (FMT), smooth muscle metaplasia (SMM) and fibrogenesis in endo- mediators contribute to impairing the endometrium further, wors- 433 bs_bs_query
374
bs_bs_query metriosis through the activation of the TGF-β1/Smad3 signalling ening the pain symptoms (Shi et al., 2016). 434 bs_bs_query
375
bs_bs_query pathway (Zhang et al., 2016a). Serial observational studies of both Among signalling pathways involved in smooth muscle contrac- 435 bs_bs_query
376
bs_bs_query mouse and baboon models of endometriosis lend strong support to tion, RhoA and ROCK-I mRNA and protein expression have a typical 436 bs_bs_query
377
bs_bs_query this idea (Zhang et al., 2016b, 2016c). In humans, evaluation of the menstrual cycle-dependent pattern in the normal JZ. Conversely, in 437 bs_bs_query
378
bs_bs_query ovarian endometrioma cyst fluid also provides data that are consis- adenomyosis, the levels of RhoA and ROCK-I are increased, without 438 bs_bs_query
379
bs_bs_query tent with this notion (Guo et al., 2015a). Also consistent with this notion, the typical cyclic change. RhoA/ROCK-I signalling may be enhanced 439 bs_bs_query
380
bs_bs_query anti-platelet therapy has been shown to be effective in mice with by oestrogens, affecting uterine JZ contraction in adenomyosis (Wang 440 bs_bs_query
381
bs_bs_query induced endometriosis (Guo et al., 2015b). In a serial experimenta- et al., 2016). 441 bs_bs_query
382
bs_bs_query tion of mouse adenomyosis, progressive EMT, FMT, SMM and 442 bs_bs_query
383
bs_bs_query fibrogenesis have been found (Shen et al., 2016). In human adeno- Inflammatory peptides and prostaglandins 443 bs_bs_query
384
bs_bs_query myosis, it has been found that indeed platelets are aggregated in A clear involvement of inflammation in the pathogenesis of adeno- 444 bs_bs_query
385
bs_bs_query adenomyotic lesions and the data are consistent with gradual but pro- myosis was suggested by the observation of high expression of IL- 445 bs_bs_query
386
bs_bs_query gressive EMT, FMT, SMM and fibrosis (Liu et al., 2016). Similar to 1β, CRH and UCN in adenomyotic nodules (Carrarelli et al., 2016). The 446 bs_bs_query
387
bs_bs_query endometriosis, anti-platelet therapy has also been found to be effi- increased expression of CRH and UCN may be part of the local re- 447 bs_bs_query
388
bs_bs_query cacious in treating mice with induced adenomyosis (Zhu et al., 2016). sponses to the invading endometrial cells. Mast cells activated by CRH 448 bs_bs_query
389
bs_bs_query Because of FMT and SMM, the enlarged uterus that is characteris- and UCN may play a role in the development of inflammation in ad- 449 bs_bs_query
390
bs_bs_query tic of adenomyosis may well be the result of platelet-driven cellular enomyosis. Because CRH/UCN has been shown to activate COX-2 in 450 bs_bs_query
391
bs_bs_query transdifferentiation. This heterogeneity and enlargement of smooth other tissues, the high expression of CRH and UCN in adenomyosis 451 bs_bs_query
392
bs_bs_query muscle cell populations in the myometrium resulting from adeno- may also lead to increased prostaglandin synthesis (Carrarelli et al., 452 bs_bs_query
393
bs_bs_query myosis may lead to increased uterine contractility on the one hand 2016). 453 bs_bs_query
394
bs_bs_query and the lack of synchronized contraction on the other, eliciting pain The hypothesis that NF-κB plays a critical role in the pathogen- 454 bs_bs_query
395
bs_bs_query perception. esis of adenomyosis is supported by the evidence of increased 455 bs_bs_query
396
bs_bs_query Other data also give credence to this view. Valproic acid, which expression of the NF-κB p65 subunit in the eutopic endometrium and 456 bs_bs_query
397
bs_bs_query has been shown to be promising in treating human adenomyosis (Liu adenomyotic nodules (Li et al., 2013). In addition, stromal cells of the 457 bs_bs_query
398
bs_bs_query
Q6 and Guo, 2008; Liu et al., 2010), turns out to be anti-platelet (David- eutopic endometrium and adenomyotic tissues showed an in- 458 bs_bs_query
399
bs_bs_query
Q7 son et al., 2011), as are resveratrol (Yang et al., 2008) and creased immunoreactivity of both nuclear and the cytoplasmic NF- 459 bs_bs_query
400
bs_bs_query andrographolide (Lien et al., 2013; Lu et al., 2011), which have been κB p65 subunit, while in the glandular cells only the nuclear staining 460 bs_bs_query
401
bs_bs_query shown to be promising in treating adenomyosis in animals (Zhu et al., of the NF-κB p65 subunit was found to be higher than in controls (Park 461 bs_bs_query
402
bs_bs_query
Q8 2015) and humans (Liu et al., 2015). et al., 2016). 462 bs_bs_query
403
bs_bs_query The mechanism of tissue traumatization and healing physiologi- 463 bs_bs_query
404
bs_bs_query Pelvic pain cally involves local production of interleukin-1 (IL-1), which induces 464 bs_bs_query
405
bs_bs_query the cyclooxygenase-2 enzyme (COX-2), causing the production of pros- 465 bs_bs_query
406
bs_bs_query Uterine contractility and oxytocin receptors taglandin E2 (PGE2). Hence, the steroidogenic acute regulatory protein 466 bs_bs_query
407
bs_bs_query Women with symptomatic adenomyosis exhibit increased uterine con- (STAR) and the P450 aromatase are activated. Thus, the aromatiza- 467 bs_bs_query
408
bs_bs_query tractility associated with dysmenorrhoea (Mao et al., 2011). In uSMCs tion of testosterone into oestradiol contributes to a local 468 bs_bs_query
409
bs_bs_query the contractile amplitude and oxytocin receptor (OTR) expression levels hyperestrogenic state with its proliferative and healing effects via the 469 bs_bs_query
410
bs_bs_query were significantly higher in women with adenomyosis than in those oestrogen receptor (ERβ) (Leyendecker et al., 2009). 470 bs_bs_query
411
bs_bs_query without, with a correlation with intensity of dysmenorrhoea (Guo et al., Hyperestrogenism was also shown to stimulate the production of 471 bs_bs_query
412
bs_bs_query 2013; Nie et al., 2010). Conceivably, a hyperactive uterus, as mani- IL-10, a cytokine with immunosuppressive abilities. High expression 472 bs_bs_query
413
bs_bs_query fested with dysperistalsis or even spasm during menstruation, coupled of IL-10 was demonstrated in both the eutopic and ectopic endome- 473 bs_bs_query
414
bs_bs_query with increased innervations, should suffice to cause dysmenorrhoea. trium of women with adenomyosis. This observation may explain the 474 bs_bs_query
415
bs_bs_query Immunohistochemical examination of both OTR and vasopressin persistence of the ectopic foci within the myometrium without elimi- 475 bs_bs_query
416
bs_bs_query receptor (VP1αR) expression in the endometrium, myometrium and nation by the immune system of the host (Wang et al., 2009). 476 bs_bs_query
417
bs_bs_query adenomyotic lesions demonstrated morphological changes and The TLR4 signalling pathway in stromal cells of the eutopic and 477 bs_bs_query
418
bs_bs_query overexpression of OTR in the adenomyosis-surrounding myome- ectopic endometrium is postulated to be essential for the pathogen- 478 bs_bs_query
419
bs_bs_query trium, while VP1αR was expressed in myometrial cells and blood esis of adenomyosis. TLR4 signalling, activated by endogenous ligands, 479 bs_bs_query
420
bs_bs_query vessels. Thus, morphological changes and increased myometrial OTR promotes the secretion of various cytokines and growth factors, stimu- 480 bs_bs_query
421
bs_bs_query expression suggest that dysperistalsis plays an essential role in the lates endometrial cell proliferation as well as recruiting and activating 481 bs_bs_query
422
bs_bs_query development of adenomyosis and dysmenorrhoea (Mechsner et al., immune cells (macrophages, DCs, NK cells). Further induction of 482 bs_bs_query
423
bs_bs_query 2010). stromal cell proliferation and invasion amplifies local inflammatory 483 bs_bs_query
424
bs_bs_query The changes in the expression or activity of potassium channels response, and eventually leads to the development of adenomyosis 484 bs_bs_query
425
bs_bs_query in uSMCs can cause inadequate membrane depolarization, result- (Guo et al., 2016) (Figure 2). 485 bs_bs_query
426
bs_bs_query ing in abnormal uterine activity (Brainard et al., 2007). In uSMCs from 486 bs_bs_query
427
bs_bs_query adenomyotic tissues, the expression of large conductance calcium- Neurogenic factors 487 bs_bs_query
428
bs_bs_query and voltage-sensitive potassium channel (BKCa)-α/β subunits and The myometrium is innervated by a subserosal plexus and a plexus 488 bs_bs_query
429
bs_bs_query voltage-gated potassium channel (Kv) 4.2 and Kv4.3 was signifi- at the endometrial–myometrial junction (Krantz, 1959). The func- 489 bs_bs_query
430
bs_bs_query cantly higher than those in the control group. The abnormal uterine tional layer of the endometrium is mainly innervated by sensory 490 bs_bs_query
431
bs_bs_query smooth muscle contractility may cause a change in the microcircu- unmyelinated C nerve fibres that may be activated or sensitized by 491 bs_bs_query
432
bs_bs_query lation of the uterus, accumulating inflammatory factors. Those inflammatory mediators released from the endometrium, resulting 492 bs_bs_query
doi: 10.1016/j.rbmo.2017.06.016
ARTICLE IN PRESS
493
bs_bs_query in neurogenic inflammation. PE2, prostacycline and norepinephrine et al., 2016), so do activated platelets, which are known to be acti- 553
bs_bs_query
494
bs_bs_query released from adrenergic fibre endings can sensitize sensory C (Apfel, vated in endometriosis (Ding et al., 2015) and adenomyosis (Shen et al., 554
bs_bs_query
495
bs_bs_query 2000). 2106). TXA2 was recently reported to be a neurotrophic factor and 555
bs_bs_query
496
bs_bs_query Zhang et al. (2009, 2010) reported the presence of PGP9.5- may be responsible for increased innervations in endometriosis (Yan 556
bs_bs_query
497
bs_bs_query positive nerve fibres in the functional layer of the endometrium of et al., 2016) (Figure 2). 557
bs_bs_query
498
bs_bs_query women with adenomyosis or uterine fibroids and associated pain symp- 558
bs_bs_query
499
bs_bs_query toms, while they were absent in those with asymptomatic adenomyosis Abnormal uterine bleeding (AUB) 559
bs_bs_query
500
bs_bs_query or uterine fibroids. Furthermore, neurofilament protein (NF)- 560
bs_bs_query
501
bs_bs_query positive cells were detected in the endometrium and myometrium of Recent evidence has shown that activin A modulated endometrial vas- 561
bs_bs_query
502
bs_bs_query women with myoma and adenomyosis, playing a potential role in pain cularization by stimulating ESCs to produce vascular endothelial growth 562
bs_bs_query
503
bs_bs_query generation (Choi et al., 2015). In addition, a positive correlation between factor (VEGF), one of the most potent angiogenic factors (Rocha et al., 563
bs_bs_query
504
bs_bs_query severity of pain and PGP9.5 and NF staining in the myometrium was 2012). Both activin and follistatin were suggested to be involved in 564
bs_bs_query
505
bs_bs_query observed in women with painful adenomyosis (Lertvikool et al., 2014). the development of dysmenorrhoea and heavy menstrual bleeding. 565
bs_bs_query
506
bs_bs_query Nerve growth factor (NGF) is involved in pain generation, neural In adenomyotic nodules, activin A, myostatin, follistatin and both activin 566
bs_bs_query
507
bs_bs_query plasticity, immune cell aggregation and release of inflammatory type II receptors are highly expressed. Compared with control en- 567
bs_bs_query
508
bs_bs_query factors. In a mouse model of adenomyosis, NGF-β and its receptors dometrium, the expression of follistatin and type II receptors is elevated 568
bs_bs_query
509
bs_bs_query expressed in the uterus and in dorsal root ganglia were found to be in eutopic endometrium from patients with adenomyosis (Carrarelli 569
bs_bs_query
510
bs_bs_query higher in the older mice-developed adenomyosis model group than et al., 2015). The increased activin A expression observed in adenomyotic 570
bs_bs_query
511
bs_bs_query in controls. The gradual increase of NGF-β and its receptor levels as nodules potentially alter the microenvironment in adenomyosis by af- 571
bs_bs_query
512
bs_bs_query the disease worsens suggests the role played by NGF-β in adeno- fecting the inflammatory response and neoangiogenesis. An autocrine/ 572
bs_bs_query
513
bs_bs_query myosis pathogenesis (Li et al., 2011). High expression of NGF, paracrine effect of these growth factors in adenomyosis is also indicated 573
bs_bs_query
514
bs_bs_query synaptophisin (SYN) and MAP2 mRNAs in adenomyotic nodules im- by the increased local ActRIIa and ActRIIb expression (Carrarelli et al., 574
bs_bs_query
515
bs_bs_query plicated possible neurogenesis in adenomyosis and its associated pain. 2015). 575
bs_bs_query
516
bs_bs_query Protein expression of CRH, NGF and SYN in adenomyotic nodules was In both eutopic and ectopic endometria of adenomyosis, the ex- 576
bs_bs_query
517
bs_bs_query also confirmed by immunohistochemical and immunofluorescence pression of MMP-2, MMP-9 and VEGF was significantly greater than 577
bs_bs_query
518
bs_bs_query analyses. Furthermore, urocortin-induced NGF mRNA expression in that in normal endometrium with a positive correlation between VEGF 578
bs_bs_query
519
bs_bs_query cultured human ESCs confirms a link between inflammatory and neu- and metalloproteinase expression. This observation suggests a role 579
bs_bs_query
520
bs_bs_query rogenic pathways (Carrarelli et al., 2016). played by MMP-2, MMP-9 and VEGF in the invasion of endometrial 580
bs_bs_query
521
bs_bs_query Mice with induced adenomyosis also show a decreased number tissues into the myometrium and in angiogenesis in adenomyotic im- 581
bs_bs_query
522
bs_bs_query of glutamate decarboxylase (GAD)65-expressing neurons with re- plants. The serum levels of VEGF in patients with adenomyosis were 582
bs_bs_query
523
bs_bs_query sulting loss of GABAergic inhibition and hyperalgesia. The number proposed to predict the prognosis of adenomyosis after interventional 583
bs_bs_query
524
bs_bs_query of these neurons is increased by treatment with epigallocatechin-3- therapies (Mu et al., 2015b). 584
bs_bs_query
525
bs_bs_query gallate (EGCG), which also reduces the expression of inflammatory Another factor involved in angiogenesis in adenomyosis is the 585
bs_bs_query
526
bs_bs_query mediators and OTR in the ectopic endometrium or myometrium, im- retinoid-interferon (IFN)-induced mortality 19 (GRIM-19). A recent study 586
bs_bs_query
527
bs_bs_query proving hyperalgesia. In addition, EGCG treatment reduces the number showed that GRIM-19 was down-regulated in the eutopic endome- 587
bs_bs_query
528
bs_bs_query of macrophages infiltrating into the ectopic endometrium, while it in- trium and the levels were further reduced in the endometrial glandular 588
bs_bs_query
529
bs_bs_query creases the expression of PR-B (Chen et al., 2013). Thus, adenomyosis- epithelial cells of adenomyotic lesions. Down-regulation of GRIM-19 pro- 589
bs_bs_query
530
bs_bs_query induced pain resembles neuropathic pain with remarkable central motes angiogenesis through the activation of both pSTAT3 (Y705) and 590
bs_bs_query
531
bs_bs_query plasticity (Chen et al., 2014). its dependent gene VEGF (Wang et al., 2016), causing a higher 591
bs_bs_query
532
bs_bs_query The glycoprotein neural cell adhesion molecule (NCAM), also known microvessel density in eutopic and ectopic endometria (Goteri et al., 2009). 592
bs_bs_query
533
bs_bs_query as CD56, is highly expressed in endometrial glandular epithelium in pa- Endothelial nitric oxide synthase (eNOS) plays an essential role 593
bs_bs_query
534
bs_bs_query tients with adenomyosis, with a positive correlation between epithelial in the occurrence of bleeding. The expression of eNOS in endome- 594
bs_bs_query
535
bs_bs_query staining intensity and dysmenorrhoea. The increased secretion of CD56 trium and myometrium specimens is higher in the uterus with 595
bs_bs_query
536
bs_bs_query stimulates nerve growth in the stroma, suggesting its role in the de- adenomyosis than that in controls. Furthermore, the expression of 596
bs_bs_query
537
bs_bs_query velopment of menstrual pain in adenomyosis (Wang et al., 2015). The eNOS is significantly higher in patients with dysmenorrhoea and men- 597
bs_bs_query
538
bs_bs_query severity of dysmenorrhoea also correlates with the Slit–Robo system, orrhagia (Oh et al., 2013). 598
bs_bs_query
539
bs_bs_query known for its role in neuronal development. Slit and Robo immunore- Tissue factor (TF) is involved in heavy menstrual bleeding and dys- 599
bs_bs_query
540
bs_bs_query activity were found to be increased in the ectopic endometrium of women menorrhoea in adenomyosis and an increased expression has been 600
bs_bs_query
541
bs_bs_query with adenomyosis and this system, with microvessel density (MVD) in shown in both eutopic and ectopic endometria, with a positive corre- 601
bs_bs_query
542
bs_bs_query the eutopic endometrium, has been reported to be a significant pre- lation with heavy menses and severity of dysmenorrhoea (Liu and Guo, 602
bs_bs_query
543
bs_bs_query dictor for dysmenorrhoea severity (Nie et al., 2011). 2011; Liu et al., 2011). This is consistent with the recent finding that plate- 603
bs_bs_query
544
bs_bs_query In adenomyotic lesions and eutopic endometrium the expres- lets are aggregated in adenomyotic lesions (Liu et al., 2016) (Figure 2). 604
bs_bs_query
545
bs_bs_query sion of Cyr61, a secreted ECM-associated signalling protein of the CCN 605
bs_bs_query
546
bs_bs_query family, is correlated with age, number of spontaneous labours, PBAC Infertility 606
bs_bs_query
547
bs_bs_query score, VAS score, uterine volume, adenomyosis type, and concur- 607
bs_bs_query
548
bs_bs_query rent endometriosis. Thus, Cyr61 may be indirectly related to the degree Adenomyosis is described as a cause of infertility and negative as- 608
bs_bs_query
549
bs_bs_query of dysmenorrhoea and involved in the pathogenesis of adenomyosis sisted reproductive technologies outcomes (Vercellini et al., 2014), 609
bs_bs_query
550
bs_bs_query (Zhang et al., 2016d). possibly due to the alteration of the normal myometrial architec- 610
bs_bs_query
551
bs_bs_query Because the ectopic endometrium is reported to secrete potent ture that disturbs the uterine environment, uterine peristalsis and 611
bs_bs_query
552
bs_bs_query platelet activators, such as thrombin and thromboxane A2 (TXA2) (Guo sperm transport (Leyendecker et al., 1996). These abnormalities even- 612
bs_bs_query
doi: 10.1016/j.rbmo.2017.06.016
ARTICLE IN PRESS
613 bs_bs_query tually result in implantation failure (Campo et al., 2012a; Sunkara and of adenomyosis, it is not proven yet that all the evidence available may 672 bs_bs_query
614 bs_bs_query Khan, 2012). be applied to different forms of the disease. However, sex steroid hor- 673 bs_bs_query
615 bs_bs_query Accumulating evidence suggests that adenomyosis is strongly as- mones, inflammation, neonagiogenesis, growth factors, ECM enzymes 674 bs_bs_query
616 bs_bs_query sociated with subfertility in reproductive age women. Dysregulation and neurogenic factors are key pathogenic mediators of pain, AUB 675 bs_bs_query
617 bs_bs_query of a number of implantation-associated factors, such as HOXA10, LIF, and infertility. More research is needed to better understand the patho- 676 bs_bs_query
618 bs_bs_query MMP2, IL-6, cytochrome P450 and RCAS1, in the eutopic endome- physiology and the early pathways implicated in the initiation of 677 bs_bs_query
619 bs_bs_query trium in women with adenomyosis leads to reduced endometrial adenomyosis, in order to develop adequate therapeutic strategies. 678 bs_bs_query
620 bs_bs_query receptivity and impaired decidualization (Campo et al., 2012b; Fischer 679 bs_bs_query
621 bs_bs_query et al., 2011; Xishi et al., 2010; Zhou et al., 2012).
680 bs_bs_query
622 bs_bs_query HOXA10 gene expression is decreased in the secretory phase en-
Uncited references Q14 681
623 dometrium of women with adenomyosis, suggesting a potential
bs_bs_query
bs_bs_query
624 bs_bs_query mechanism for impaired implantation observed in these women 682 bs_bs_query
625 bs_bs_query (Fischer et al., 2011). Similarly, a dysregulation of leukaemia inhibi- Barrier et al, 2004, Choi et al, 2010, Garcia-Segura, 2008, 683 bs_bs_query
626 bs_bs_query tory factor (LIF) in the endometrium and uterine flushing fluid of Laoag-Fernandez et al, 2003, Li et al, 2006, Tokushige et al, 2006 684 bs_bs_query
627 bs_bs_query women with adenomyosis has been observed during the implanta- 685 bs_bs_query
628 bs_bs_query tion window (Xiao et al., 2013). Orphan nuclear receptor NR4A is a A R T I C L E I N F O 686 bs_bs_query
629 bs_bs_query novel regulator of decidualization, acting as ligand-independent tran- 687 bs_bs_query
630 bs_bs_query scription factor and activating target genes in human ESCs. In Article history: 688 bs_bs_query
631 bs_bs_query adenomyotic tissues, down-regulation of NR4A receptor and FOXO1A Received 22 December 2016 689 bs_bs_query
632 bs_bs_query were found to impair decidualization (Jiang et al., 2016b). Received in revised form 13 April 2017 690 bs_bs_query
633 bs_bs_query Inflammation is another key factor mediating adenomyosis-associated Accepted 13 June 2017 691 bs_bs_query
634 bs_bs_query infertility. An increased expression of IL-1β and CRH in the eutopic en- Declaration: The authors report no 692 bs_bs_query
635 bs_bs_query dometrium of patients with adenomyosis suggests an involvement of financial or commercial conflicts of 693 bs_bs_query
636 bs_bs_query endometrial inflammatory pathways in infertility (Carrarelli et al., 2016). interest. 694
695
bs_bs_query
637
bs_bs_query
bs_bs_query Indeed, the cellular and humoral immunity in a eutopic endometrial mi-
696 bs_bs_query
638 bs_bs_query croenvironment in adenomyosis and in the endometrium of unaffected

Keywords: 697 bs_bs_query
639 bs_bs_query women has been shown to be different (Benagiano et al., 2014). In-
Adenomyosis 698 bs_bs_query
640 bs_bs_query creased free radical metabolism with release of reactive oxygen species
Fibrosis 699 bs_bs_query
641 bs_bs_query by macrophages and altered expression of endometrial pro-oxidant and

Infertility 700 bs_bs_query
642 bs_bs_query anti-oxidant enzymes are signals of increased inflammatory re-

Neuroangiogenesis 701 bs_bs_query
643 bs_bs_query sponses in the endometrium of adenomyosis (Ishikawa et al., 1993; Ota
Proliferation 702 bs_bs_query
644 bs_bs_query et al., 1998; Van Langendonckt et al., 2002).

Sex steroid hormone receptors 703 bs_bs_query
645 bs_bs_query The eutopic endometrium displays a dysregulation of immune

646 bs_bs_query factors, markers of apoptosis or proliferation, inflammatory media- 704 bs_bs_query
647 bs_bs_query tors, and oxidative stress with low uterine receptivity (Campo et al., REFERENCES 705 bs_bs_query
648 bs_bs_query 2012a). Members of the integrin family of cell adhesion receptors play 706 bs_bs_query
649 bs_bs_query a vital role in cell–cell interactions at the conceptus–endometrial in- 707 bs_bs_query
650 bs_bs_query terface, involving the participation of extracellular matrix. Integrin β3 Apfel, S.C., 2000. Neurotrophic factors and pain. Clin. J. Pain 16, S7– 708 bs_bs_query
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652 bs_bs_query plantation and, together with osteopontin (OPN), its main ligand, has Barrier, B.F., Malinowski, M.J., Dick, E.J., Hubbard, G.B., Bates, G.W., 710 bs_bs_query
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654 bs_bs_query trium of adenomyotic patients, integrin β3 and OPN levels were infertility. Fertil. Steril. 82, 1091–1094. doi:10.1016/ 712 bs_bs_query
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Benagiano, G., Habiba, M., Brosens, I., 2012. The pathophysiology of 714 bs_bs_query
656 bs_bs_query In adenomyosis, a number of cellular and humoral immune re- uterine adenomyosis: An update. Fertil. Steril. doi:10.1016/ 715 bs_bs_query
657 bs_bs_query sponses are observed, causing an immunological ‘vicious cycle’ in the j.fertnstert.2012.06.044. 716 bs_bs_query
658 bs_bs_query endometrium. The activation of the immune system includes the ex- Benagiano, G., Brosens, I., Habiba, M., 2014. Structural and molecular 717 bs_bs_query
659 bs_bs_query pression of cell surface antigens or adhesion molecules, an increased features of the endomyometrium in endometriosis and 718 bs_bs_query
660 bs_bs_query number of macrophages, and deposition of immunoglobulins and adenomyosis. Hum. Reprod. Update 20, 386–402. doi:10.1093/ 719 bs_bs_query
661 bs_bs_query complement components. In addition, endometrial cells expose heat humupd/dmt052. 720 bs_bs_query
Bergeron, C., Amant, F., Ferenczy, A., 2006. Pathology and 721 bs_bs_query
662 bs_bs_query shock proteins, showing signs of immunological stress and autoan-
physiopathology of adenomyosis. Best Pract. Res. Clin. Obstet. 722 bs_bs_query
663 bs_bs_query tibodies are found very frequently in the peripheral blood of women Gynaecol. doi:10.1016/j.bpobgyn.2006.01.016. 723 bs_bs_query
664 bs_bs_query with adenomyosis (Ota et al., 1998). These abnormal immune re- Brainard, A.M., Korovkina, V.P., England, S.K., 2007. Potassium 724 bs_bs_query
665 bs_bs_query sponses are proposed to be involved in poor reproductive performance channels and uterine function. Semin. Cell Dev. Biol. doi:10.1016/ 725 bs_bs_query
666 bs_bs_query in adenomyosis (Ota and Igarashi, 1993) (Figure 2). j.semcdb.2007.05.008. 726 bs_bs_query
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characterized by bleeding. Am. J. Obstet. Gynecol. 176, 263–267. 728 bs_bs_query
668 bs_bs_query Conclusions doi:10.1016/S0002-9378(97)70482-4. 729 bs_bs_query
Campo, S., Campo, V., Benagiano, G., 2012a. Adenomyosis and infertility. 730 bs_bs_query
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670 bs_bs_query The pathogenic mechanisms of adenomyosis development are still Campo, S., Campo, V., Benagiano, G., 2012b. Infertility and adenomyosis. 732 bs_bs_query
671 bs_bs_query unclear and, because there are different phenotypical expressions Obstet. Gynecol. Int. 2012, 786132. doi:10.1155/2012/786132. Q9 733 bs_bs_query
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Pathogenesis of Adenomyosis: An Update On Molecular Mechanisms

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ARTICLE IN PRESS

3 bs_bs_query Pathogenesis of adenomyosis: an update on molecular

27 bs_bs_query KEY MESSAGE

43 bs_bs_query * Corresponding author.

myometrium through an altered or absent junctional zone (JZ) 108 bs_bs_query

68 bs_bs_query endometriosis interna. Nevertheless, they are considered as two dis-

regulation of progesterone receptors, a loss of their action and ﬁnally 239

197 bs_bs_query Sex steroid hormone aberrations

198 bs_bs_query Steroid hormones are involved in the pathogenesis of adenomyosis.

2012). 346 bs_bs_query

638 bs_bs_query croenvironment in adenomyosis and in the endometrium of unaffected

641 bs_bs_query by macrophages and altered expression of endometrial pro-oxidant and

642 bs_bs_query anti-oxidant enzymes are signals of increased inﬂammatory re-

644 bs_bs_query et al., 1998; Van Langendonckt et al., 2002).

645 bs_bs_query The eutopic endometrium displays a dysregulation of immune

Brosens, I.A., 1997. Endometriosis–A disease because it is 727 bs_bs_query

668 bs_bs_query Conclusions doi:10.1016/S0002-9378(97)70482-4. 729 bs_bs_query

Reprod. Biomed. Online doi:10.1016/j.rbmo.2011.10.003. bs_bs_query

746 bs_bs_query 1933719113488455. Reprod. Sci. 23, 1044–1052. doi:10.1177/1933719116630428. 814

751 bs_bs_query 1933719113518984. 1933719116650758. 819

785 bs_bs_query 2826.2008.01713.x. 75, 770–784. 853

790 bs_bs_query 163. doi:10.1093/humupd/dmv051. 18, 694–699. doi:10.1093/humrep/deg179. 858

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