Complicatii Urologice.pdf

Int Urol Nephrol DOI 10.1007/s11255-016-1248-5

UROLOGY - REVIEW

Urological complications of uterine leiomyoma: a review of literature Gautam Dagur1 · Yiji Suh1 · Kelly Warren1 · Navjot Singh1 · John Fitzgerald2 · Sardar A. Khan1,2,3 

Received: 13 January 2016 / Accepted: 13 February 2016 © Springer Science+Business Media Dordrecht 2016

Abstract  Introduction  Uterine leiomyomas are common gynecologic tumor in reproductive-aged women, by age 50, diagnosis shared by urologist, gynecologists and radiologists. Objective  The goal of this article is to review the current literature, study the impact of leiomyoma on female lower urinary tract, examine the cause female sexual dysfunction and provide a comprehensive review of current diagnostic, imaging studies, and current treatment of leiomyoma. Methods  Clinical leiomyoma studies published from 1956 through 2015 were identified using the PubMed search engines and the key words leiomyoma, fibroid in the current literature. Impact of leiomyoma on the lower urinary tract including female sexual dysfunction was reviewed with terms of “urinary retention”, “bladder”, “urethra”, “dyspareunia”, “incontinence”, “incomplete bladder emptying”, “female sexual dysfunction”, and “lower urinary tract” to study the urological and sexual effects of leiomyoma. Literature related to leiomyoma was reviewed from 1965 to present. Results  Women with uterine leiomyomata complained of pelvic pain, menstrual irregularities, infertility, lower urinary tract symptoms and sexual dysfunction. Conclusion  Leiomyoma is a common tumor of the uterus that often clinically impacts on the lower urinary tract and

* Sardar A. Khan [email protected] 1

Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, NY 11794, USA

2

Department of Urology, SUNY at Stony Brook, Stony Brook, NY 11794, USA

3

HSC Level 9 Room 040 SUNY at Stony Brook, Stony Brook, NY 11794‑8093, USA



results in urological and sexual symptoms. Leiomyoma can compress and grow into and become adherent to the bladder and surrounding pelvic organs or metastasize into peritoneal organs. Leiomyoma can enlarge and compress the urinary bladder, urethra, and lower end of the ureters. Leiomyoma can cause embarrassing sexual dysfunction in females. Current literature of non-surgical and surgical therapy of leiomyoma is described. Keywords  Uterine leiomyoma · Hydronephrosis · Acute urinary retention · Hematuria · Hysterectomy · Lower urinary tract symptoms Abbreviations ECM Extracellular matrix Bcl-2 Beta cell lymphoma-2 GPER G-protein estrogen receptors AUR Acute urinary retention LUTS Lower urinary tract symptoms BN Barrington’s nucleus

Introduction Uterine leiomyomas are benign neoplasms of smooth muscle that originate in the myometrium [1]. They are also known as fibroids, referring to the amount of collagen found within the masses. Incidence of leiomyomas can be as high as 70–80 % in women by age of 50, with highest rates among African-American women [2]. Leiomyomas can become symptomatic, with greater incidence among nulliparous women. Although specific causes of uterine leiomyomas are unknown, leiomyomas may be due to hormonal and genetic factors [3, 4]. Our objective is to compile recent literature to provide a comprehensive understanding

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of uterine leiomyoma as well as its urological manifestations and complications of the urinary tract. Clinical manifestations of uterine leiomyoma on female urinary tract have not been addressed in major textbooks.

Molecular and genetic aspects of uterine leiomyomas The specific etiology of leiomyomas is currently unknown, but studies suggest that leiomyoma may arise by phenotypic mutation of a single myometrial smooth muscle cell, which stimulates cell proliferation and results in production of excess extracellular matrix (ECM). Leiomyomas create a hyperestrogenic environment necessary for leiomyoma growth and maintenance. Leiomyomas have high concentrations of estrogen and progesterone receptors which assists in greater estradiol binding [5]. Increased estrogen and progesterone production leads to leiomyoma growth; therefore, it is not uncommon for women on oral contraceptive to see increased growth of leiomyomas [6, 7]. In the past, progesterone influenced the production of leiomyoma with apoptosis and generation of extraneous cells. However, Bulun et al. [3] suggests progesterone may have a role in the growth of leiomyomas. Highly expressed beta cell lymphoma-2 (Bcl-2) is able to prevent apoptosis. This gene is prevalent during the secretion phase of the menstrual cycle and less when progesterone is released. Increase in Bcl-2 protein may be the cause of increased cell growth by prevention of cell death [8]. ECM proliferation, in uterine leiomyomas, is upregulated by the promoter protein TGFβ3 [9] which is known to interact with dermatopontin and thrombospondin [10]. Integrin proteins play a critical role in the shape and growth of leiomyomas. The most critical integrin protein is integrin β1, which is upregulated in leiomyomas [11]. Alterations in chromosomes have been linked to leiomyoma growth. Chromosomes 6, 7, 12, and 14 are found to correlate with rates of leiomyoma growth [12]. Mehine et al. [4] suggest that there are four emerging molecular classifications: high rates of MED12 gene mutations, deletions of COL4A5-COL4A6 genes, increased HMGA2 expression, and FH inactivation. More studies are necessary to comprehend the genetic pathogenesis of uterine leiomyoma. Wu et al. state G-protein estrogen receptors (GPER) play an important role in tamoxifen-related uterine pathology, causing thickening and bleeding of the endometrium. Tamoxifen is a selective estrogen receptor modulator that functions as an agonist and antagonist depending on the target tissue. In endometrium, tamoxifen works as an estrogen receptor antagonist. Changing estrogen receptor-α and isoforms of the receptor along with G-protein-coupled receptor 30 in endometrial cells has been proven to control

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tamoxifen in cancer cell creation [13]. Although this study conducted focused primarily on breast cancer progression, there may be a correlation with uterine leiomyomas as the GPER in cancerous fibroblasts can produce collagen that eventually metastasizes to uterine walls. It is also interesting to note that elevation of estrogen levels correlate not only to breast cancer but also to uterine leiomyomas [14]. Targeting future research on GPER represents possible development for future potential uterine leiomyoma therapy.

Anatomical classification of leiomyomas Leiomyomas are divided based on location and position in the uterus (Table 1).

Clinical examination Symptoms Leiomyomas tend to be asymptomatic in most women but a third of women experience further growth and symptoms (Table 2). Physical examination Physical examination may fail to detect small leiomyomas. Palpation of leiomyoma is dependent on the anatomical Table 1  Anatomical classification of leiomyomas Extrapelvic leiomyoma

Intrapelvic leiomyoma

Round ligament myomata [15]

Intramural myomata [16] Submucosal myomata [16]  Protruding myomata [17] Subserosal myomata [18, 19] Pedunculated myomata  Subserosal [18]  Submucosal [17] Parasitic myomata [1, 20] Interstitial myomata [21] Cervical myomata [22] Broad ligament myomata [23]

Table 2  Common symptoms of uterine leiomyomas Symptoms  Menorrhagia [24]  Pelvic discomfort [25]  Dysmenorrhea [26, 27]  Infertility [28]  Miscarriage [29, 30]

Int Urol Nephrol Table 3  Imaging modalities for uterine leiomyomas

Table 4  Instrumentation for diagnosis of uterine leiomyomas

Imaging modalities Dynamic real time transvaginal ultrasound [31, 32]  With empty bladder  With bladder distension Abdominal ultrasound [31] Transrectal ultrasound [33]  With bladder distension  With empty bladder Plain radiography [19] Computerized tomography (CT) [34] CT with 3-dimensional reconstruction Magnetic resonance imaging (MRI) [34, 35] Stand up MRI with valsalva MRI with 3-dimensional reconstruction MR angiogram [36]

Instruments for diagnosing  Hysteroscopy [37]  Speculum examination [38]  Cystoscopy [39]  Diagnostic laparoscopy [40]

Hysterosalpingography [19]

 Video-urodynamics

angiogenesis occurs upon protruding onto the bladder, and contraction of the bladder ruptures these vessels which may result in hematuria. Parasitic leiomyoma dislodges from their site of origin and can travel to a different region of the body. Certain times, they can result in unilateral ureteral obstruction [43]. Uterine leiomyoma, growing superiorly, can protrude onto the ureter and result in obstruction. This may cause urine backflow and hydronephrosis. Urethral obstruction

location of leiomyoma. Bimanual pelvic examination, including rectal and pelvic examination, may reveal palpable leiomyoma with pelvic tenderness. Speculum examination and optional proctoscopy may complete the physical diagnosis.

Imaging methods Leiomyomas are often detected during a pelvic exam. However, imaging studies are utilized to identify anatomical locations, size, and impact on urinary tract (Table 3).

Instrumental exam Diagnosis for leiomyomas with instruments and videourodynamics helps identify their anatomical locations and impact on bladder-urethra and upper urinary tract (Table 4).

Urological complications of leiomyomas Pathogenesis of urological complications Urological complications may develop depending on the anatomical locations, size, growth, and the leiomyoma sarcomatous changes. Growth of a leiomyoma in the broad ligament can result in obstruction of the bladder outlet and paravaginal obstruction, resulting in urinary retention [41]. Intrapelvic leiomyoma can protrude anteriorly and inferiorly from the uterus and press onto the bladder. Leiomyomas rely on angiogenesis to allow for growth [42]. Therefore,

Several case reports describe acute urinary retention (AUR) in patients with leiomyoma [13, 44, 45]. Yazdany et al. [46] states, AUR can be caused when uterine leiomyomas cause a superior and anterior rotation of the cervix, which ultimately causes urethral or bladder-neck compression. During urination, the cervix rotates away from the urethra. Proposed mechanism relating AUR secondary to uterine leiomyomas results from obstruction of proximal urethra and bladder neck, associations with premenstrual pelvic congestion, and neuropathy of the pudendal or sacral nerves [13]. Angle variations of the bladder neck and urethral mobility demonstrate the physical differences between continent and incontinent women. Straining while in the supine position does not cause obstruction in the urethral range of motion as the average rotational angle of the bladder neck ranges from 21° to 44°, with an average of 32°. The bladder neck angle, the angle of the urethrovesical junction located behind the pubic symphysis, ranges at a normal level between 83° and 107° with an average of 95°. In contrast, continent pregnant females have different ranges of −8° to 56° with an average of 19° for the urethral mobility, and a range of 38°–80° with an average of 65° for the resting bladder neck angle. The range of urethral mobility is more limited in incontinent patients, while bladder neck angle is greater in range [47, 48]. If untreated, AUR can result in permanent damage to the detrusor muscle, resulting in bladder trabeculation, bladder diverticula, and vesicoureteral reflux [49]. Ureteral obstruction/hydronephrosis Patients with uterine leiomyoma can develop obstructive uropathy, either unilateral or bilateral secondary

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ureteral obstruction causing hydronephrosis. Mirsadraee et al. discuss 10 patients suffering from hydronephrosis. Patient complaints include menorrhagia, dysmenorrhea, pain, and mild renal impairment. In all cases, large leiomyomas compressed the ureter at the pelvic brim. Uterine artery embolization resolved the hydronephrosis and relieved ureteral obstruction, relieving symptoms as well [50]. Lai et al. [51] suggest that hypertension, resulting from obstruction of the kidneys, leads to decreased glomerular filtration rate by increased pressure in the Bowman’s capsule. More studies are necessary to determine the relationship between hypertension and hydronephrosis. Prolonged uterine prolapse, due to uterine leiomyoma, can result in hydronephrosis [52]. Lower urinary tract symptoms (LUTS) Stewart et al. present a case in which a woman experiences heavy menstrual bleeding, nocturia, and urinary frequency. Diagnostic study indicated uterine leiomyoma could potentially have caused these symptoms [53]. Parker-Autry et al. conducted a survey where patients with uterine leiomyoma experience LUTS. Study was concluded due to the location and type of leiomyoma. Patients with intramural leiomyoma and anterior fibroids had worse symptoms of LUTS. More prominent symptoms included: nocturia, urinary urgency, frequency, and incontinence [54]. It can be concluded that bladder compression due to anterior leiomyoma resulted in LUTS (Fig. 1). Vesicouterine fistula A degenerating leiomyoma or leiomyosarcoma can cause a fistula between the uterus and bladder, causing hematuria, abdominal pain, and vaginal urine leakage [39]. Fistulas may be confirmed with cystoscopy, cystogram methylene blue test, or CT scan. Surgery is the preferred treatment, utilizing omental flap interpositions in certain situations [55]. Renal failure If uterine leiomyomas are left untreated for prolonged period of time, it could result in renal failure and renal hypertension [56]. Leiomyoma may cause renal impairment with good prognosis [57].

Fig. 1  Uterine leiomyoma, identified by the arrow, compressing and adhering to the bladder presenting irritative and obstructive urinary symptoms. This can interfere with storage and emptying of the bladder

Female sexual dysfunction Masters and Johnson reported four stages of the female sexual cycle which consisted of excitement, plateau, orgasm, and resolution [59]. Female sexual response results in increased pelvic blood flow, vaginal lubrication, and clitoral and labial engorgement. Increase in pelvic blood flow is by hypogastric arterial bed [60]. Barriers to sexual function in female patients with leiomyoma include pelvic pain, dyspareunia, orgasmic disorders, decreased libido, decreased vaginal lubrication, urinary incontinence, and obstructive and irritative bladder symptoms. Sexual dysfunction can occur secondary to uterine leiomyomas when a large retroperitoneal mass impinges upon the vagina. Repetitive contact can irritate the lumen of the vagina, as projecting parietal peritoneum cause pain and discomfort [61]. Currently, there is no treatment for dyspareunia, which makes surgery an option. Eight months are needed after surgery to resume normal sexual intercourse [62]. Nerve sparing surgery of leiomyomas may preserve sexual function in females [63].

Hematuria Neurogenic bladder Hematuria may be a significant manifestation of leiomyoma, invading the bladder wall during degeneration, sarcomatous changes, and vesico-uterine fistula [39, 58].

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Increased pressure within the bladder acts on the proprioceptive sensory receptor signals onto the Barrington’s

Int Urol Nephrol Table 5  Non-urological complications of uterine leiomyomas Non-urological complications Cystic degeneration [65] Torsion of uterine leiomyomas [40, 66] Colorectal/anal difficulty [67] Circulatory problems  Deep-vein thrombosis [68, 69]  Polycythemia [70]  Pelvic venous compression [71]  Intravenous leiomyomatosis [25, 70]  Thrombus extending into Right Heart [72]  Thrombus extending into vena cava [73]  Thrombophlebitis [74]  Edema [75] Leiomyomatosis peritonealis disseminata [76] Pregnancy complications  Miscarriage [29, 30]  Prevention of implantation/infertility [77] Uterine Prolapse [78]

nucleus (BN), within the brain. BN relays to the hypothalamus and responding back to bladder to void. Both parasympathetic and sympathetic signaling aid in the contraction of the bladder wall and relaxation of internal sphincter, resulting in micturition [64]. Disruption of the pelvic autonomic pathways can result in neurogenic bladder and voiding dysfunction. Leiomyoma can compress the bladder and increase signaling of proprioceptive sensory receptors, therefore causing increased frequency of micturition [44]. Leiomyomas can also lead to urethral obstruction depending on the location of the growth [44].

Other complications of uterine leiomyomas Other, non-urological complications may present themselves due to uterine leiomyomas (Table 5).

Treatment options

Anemia [79]

Table 6  Different treatment option for uterine leiomyomas Treatment Options Hormone therapy  Levonorgestrel-releasing intrauterine device [80]  Gonadotropin-releasing hormone agonist [81]  Progesterone-receptor modulators   Mifepristone [82]   Ulipristal acetate [83]   Asoprisnil [84]  Aromatase inhibitor   Letrozole [85] Hifu of myoma [86] Surgical procedures  Minimally invasive   Hysteroscopy [87]   Uterine artery embolization [88, 89]   MRI-guided focused ultrasound surgery [90, 91]  Invasive   Myomectomy    Open [92]    Laparoscopy [93]    Robotic [94]   Hysterectomy [53, 95] Radiofrequency ablation [96] Guizhi Fuling Formula [26]

Pre-operative preparation for surgical management of complicated uterine myomectomy or excision of leiomyoma includes indwelling Foley catheter and insertion of ureteral stents to identify and prevent ureteral injury during complicated surgery. Treatment options for management of uterine leiomyomas range from observations and medical management to invasive surgical options. The type of treatment used for a patient is dependent on several factors: age, health, symptoms, menopausal status, type of fibroids, if pregnant, and choice of future pregnancy (Table 6). Surgical controversies exist regarding best treatment options.

Summary This paper examines the current literature of clinical manifestations and impact of leiomyoma on urinary tract. Diagnostic and therapeutic options to relieve urologic symptoms are discussed. Acknowledgments  We gratefully acknowledge literature research assistance from Mrs. Wendy Isser and Ms. Grace Garey. Author’s contributions  Gautam Dagur M.S. designed, organized, and wrote the review article; corrected references; and solved queries related to scientific publications from the journals. Yiji Suh wrote the review article and designed outline. Kelly Warren Ph.D. critiqued and applied logical reasoning to the literature. Navjot Singh performed Medline searches, critiqued, and corrected the literature. John Fitzgerald M.D. retrieved and evaluated scientific information related to the article. Sardar A. Khan M.D. FRCS FACS is the corresponding author, formulated clinical concepts, reviewed the article, and corrected the references.

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Compliance with ethical standards  Conflict of interest  The authors declare they have no conflict of interest.

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