New findings in the study of the pathogenesis of 2 urethral pain syndrome 3

: Urethral pain syndrome (UPS) is still a pathology in which the diagnosis is formulated as 15 a "diagnosis of exclusion". The exact pathogenetic mechanisms are not yet fully understood and 16 clear recommendations for the prevention and treatment of UPS are absent. The goal of the study was to assess the condition of the tissues in the female urethra in UPS, by using transvaginal ultrasound (TVUS) and cross-polarization optical tomography (CP OCT). TVUS showed an expansion in the diameter of the internal lumen of the urethra, especially in the proximal region compared with the norm. Compression elastography revealed areas with increased stiffness (presence of fibrosis) in urethral and surrounding tissues. When studied with CP OCT it was shown that with UPS, the structure of the tissues in most cases was changed: trophic alterations in the epithelium (hypertrophy or atrophy) and fibrosis of underlying connective tissue were observed. The proximal fragment of the urethra with UPS underwent changes identical to those of the bladder neck. This paper showed that the introduction of new technology — CP OCT — in 26 conjunction with TVUS will allow verification of structural changes in tissues of the lower urinary 27 tract at the level of their architectonics and will help doctors understand better the basics of the UPS 28 pathogenesis.


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pain syndrome management being applied.

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The close embryological relationship between the urethra and the bladder makes it likely that 52 there are causes in common with the development of painful bladder syndrome [7]. According to the 53 classification of the International Association for the Study of Pain (IASP, 2019) the mechanism of 54 CPP and possible causes of its occurrence may include vascular lesions, persistent inflammatory 55 processes, or violation of the innervation of organs due to mechanical compression in the pelvic 56 region, but often the reason is not clear [8].

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The connective tissue matrix of organs plays a key role in the occurrence and persistence of pain, 58 as shown by the works of a number of authors [9,10]. It is believed that connective tissue, as well as 59 performing its supporting, protective and trophic functions, acts as a network-wide 60 mechanosensitive signaling system -as a global unifying network [9,11].

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Thus, it can be surmised that the above reasons for the development of CPP could well be due 62 to factors that affect the state of the connective tissue matrix of the lower urinary tract. However,

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there are currently no methods for adequate, appropriate study of the structure of urethral tissues.

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According to the standards for examination of patients with CPP when using the UPOINT

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High spatial resolution (5-15 µ m) and easy performing with minimal expertise are the main 81 advantages of OCT in contrast to US. The endoscopic nature of OCT probes not only enhances 82 patient comfort and safety but also makes it especially suitable for assessing narrow tubular organs 83 as well as using standard guidewires for examining deeply located objects in the body [16].

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CP OCT is a functional extension of OCT that enables the detection of changes in the state of 85 polarization of light caused by birefringence and coupling between two polarization states due to 86 scattering in the random media (cross-scattering) [17]. As a result, two types of images are obtained 87 simultaneously: in the initial (co-) polarization and orthogonal (cross-) polarization, which allow 88 assessing isotropic (cells) and anisotropic (collagen and elastic fibers of connective tissue) structures 89 separately [18,19]. This is important in cases when precise observation only connective tissue 90 structures are needed.

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The goal of the study was to assess the condition of the tissue in the female urethra in UPS, by

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Informed consent to participate in the study was obtained from the participants.

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Compression elastography is a technique that displays the relative deformation of tissues in the form 120 of their color mapping in real time [20]. When the tissue is subjected to an external force 121 (deformation), the harder/denser areas of the tissue exhibit relatively less compression than the 122 softer areas. In our study, on the ultrasound elastographic images, the adjustment scale was set to 123 display the harder areas in blue, with the softer areas appearing in red.

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After an independent blind visual assessment of the CP OCT images, the «UPS» group was 161 divided into 2 age subgroups: patients under 50 and those over 50.

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Hormonal abnormalities (94.8%) were found in 24 sexually active women in the pre-menopausal

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The premorbid background in patients with UPS was neurological pathology (63.6%), and these 176 are diseases associated with the involvement of the peripheral nervous system and, as is important,

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with the state of the psycho-emotional sphere.

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Thus, in all patients with UPS, an increase in the diameter of the internal lumen of the urethra, 214 especially in the proximal region, was recorded.

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In 7 (29.1%) cases pathological changes were recorded in the urethral tongue, a cavernous 216 structure that, as the bladder fills, normally increases in volume due to becoming engorged with 217 blood and, together with the sphincter trigonalis, closes the exit from the bladder into the urethra.  processes in these tissues (Fig. 5 a1, b1). The signal from the connective tissue structures in 258 cross-polarization has a noticeable local decrease in intensity caused by the shadows of dilated blood 259 vessels and by tissue edema (Fig. 5 a2, b2). In the middle and distal parts of the urethra, by contrast, 260 thinning of the epithelium is noticeable (Fig. 5 c1, d1), while in the middle part, the border with the 261 underlying connective tissue layer is clear (Fig. 5 c1). The connective tissue layer is thickened (Fig. 5 262 c2, d2) and looks more homogeneous in structure (Fig. 5 c2)  266 Figure 6 shows an example of patient E., 60 years old with UPS lasting 5 years. In the bladder 267 neck and proximal urethra (Fig. 6 a1, b1), as well as in the rest of the urethra (Fig. 6 c1, d1), the 268 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 26 September 2020 doi:10.20944/preprints202009.0623.v1 9 of 13 epithelium is atrophic; in places where it is partially preserved, the border of the epithelium with the 269 underlying connective tissue layer is blurred (Fig. 6 a1, d1). The signal from connective tissue 270 structures in cross-polarization is weak, presumably due to severe tissue edema (Fig. 6 a2-c2). In the 271 distal urethra, on the other hand, the connective tissue layer exhibits cross-scattering, but appears 272 homogeneous in structure (Fig. 6 d2) compared to normal (Fig. 4 d2). In this subgroup of patients,

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The results of the incidence of the bladder neck + proximal conditions are presented in Table 3.    Of the 11 cases of hyperplasia detected in the proximal urethra, only in the case of the 293 epithelium was there also thickening in the middle and distal urethra. In other situations, atrophy 294 was recorded -4 cases, while, in 6 the epithelium was of normal thickness. In the presence of 295 atrophy in the proximal urethra (n = 11), atrophy was recorded in the underlying regions -5 cases,

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while the epithelium was of normal thickness in 6 cases.

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Thus, the CP OCT method allowed us non-invasively to determine the state of the epithelium 298 and connective tissue structures of the bladder neck and urethra in vivo. It was shown that with UPS, 299 the structure of the tissues in most cases is changed. In this case, the proximal fragment of the 300 urethra with UPS undergoes changes identical to those of the bladder neck.

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UPS is still a pathology in which the diagnosis is formulated as a "diagnosis of exclusion".

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There is reason to believe that the cause of the development of chronic inflammatory processes

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Thus, it has been shown that there are many factors that cause persistent long-term pain in the 382 urethral region, or that contribute to the intensification of pain, some of which have yet to be studied.

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Given the non-obviousness of the causes of UPS, new research protocols and additional imaging and