Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine fibroids
2009; Elsevier BV; Volume: 92; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2009.05.016
ISSN1556-5653
AutoresXinmei Zhang, Bangchun Lu, Xiufeng Huang, Hong Xu, Caiyun Zhou, Jun Lin,
Tópico(s)Gynecological conditions and treatments
ResumoTo determine whether nerve fibers in the functional layer endometrium are caused by an endometriosis itself or a common symptom of pain, endometrial tissues from 30 women with endometriosis, 40 women with adenomyosis, 41 women with uterine fibroids, and 47 endometriosis women with adenomyosis were stained immunohistochemically using the highly specific polyclonal rabbit antiprotein gene product 9.5 (PGP9.5) and monoclonal mouse antineurofilament protein. We demonstrated PGP9.5-immunoactive nerve fibers in the functional layer of endometrium in women with pain symptoms, but not in women without pain symptoms, whether the women had endometriosis, adenomyosis, uterine fibroids, or endometriosis with adenomyosis, suggesting a role of PGP9.5-immunoactive nerve fibers in the functional layer of the endometrium playing in pain generation in these disorders. To determine whether nerve fibers in the functional layer endometrium are caused by an endometriosis itself or a common symptom of pain, endometrial tissues from 30 women with endometriosis, 40 women with adenomyosis, 41 women with uterine fibroids, and 47 endometriosis women with adenomyosis were stained immunohistochemically using the highly specific polyclonal rabbit antiprotein gene product 9.5 (PGP9.5) and monoclonal mouse antineurofilament protein. We demonstrated PGP9.5-immunoactive nerve fibers in the functional layer of endometrium in women with pain symptoms, but not in women without pain symptoms, whether the women had endometriosis, adenomyosis, uterine fibroids, or endometriosis with adenomyosis, suggesting a role of PGP9.5-immunoactive nerve fibers in the functional layer of the endometrium playing in pain generation in these disorders. Although increasing evidence has demonstrated nerve fibers in the functional layer of endometrium in women with endometriosis (1Al-Jefout M. Andreadis N. Tokushige N. Markham R. Fraser I. A pilot study to evaluate the relative efficacy of endometrial biopsy and full curettage in making a diagnosis of endometriosis by the detection of endometrial nerve fibers.Am J Obstet Gynecol. 2007; 197: 578.e1-578.e4Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 2Tokushige N. Markham R. Russell P. Fraser I.S. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis.Fertil Steril. 2007; 88: 795-803Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 3Tokushige N. Markham R. Russell P. Fraser I.S. High density of small nerve fibers in the functional layer of the endometrium in women with endometriosis.Hum Reprod. 2006; 21: 782-787Crossref PubMed Scopus (163) Google Scholar), it is still a controversy whether nerve fibers in the functional layer of the endometrium are caused by an endometriosis itself or a common symptom of pain in this disorder (4Quinn M.J. Endometrial nerve fiber proliferation in "endometriosis".Am J Obstet Gynecol. 2008; 199: e13-e14Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Most recently, we found that protein gene product (PGP) 9.5-immunoactive nerve fibers in the functional layer of the endometrium were only present in women with pain symptoms, but not in women without pain symptoms, whether the women had adenomyosis or uterine fibroids (5Zhang X. Lu B. Huang X. Xu H. Zhou C. Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids.Fertil Steril. 2009 Apr 13; ([Epub ahead of print])Google Scholar). Because adenomyosis or uterine fibroids, like endometriosis, is an estrogen-dependent disease, we hypothesized that PGP 9.5-immunoactive nerve fibers in the functional layer of the endometrium are caused by a common symptom of pain rather than by an endometriosis disease itself. Endometrial tissues were collected from 30 women with endometriosis alone who underwent laparoscopy combined with hysteroscopy and diagnostic curettage, and from five endometriosis patients with adenomyosis who underwent laparoscopic hysterectomy. Of the 30 women with endometriosis alone, 18 women (mean age = 33.6 years; range = 25–39) complained of dysmenorrhoea and a range of related pain symptoms, and 12 women (mean age = 34.3 years; range = 26–39) had no pain symptoms. Of the five endometriosis patients with adenomyosis (mean age = 37.3 years; range = 35–39), three had dysmenorrhoea, and two had no pain symptoms. Endometriosis was staged according to the revised American Fertility Society score (6American Society for Reproductive MedicineRevised American Society for Reproductive Medicine classification of endometriosis: 1996.Fertil Steril. 1997; 67: 817-821Abstract Full Text PDF PubMed Scopus (2205) Google Scholar). Histologic sections of formalin-fixed and paraffin-embedded tissues including intact endometrium were obtained from 42 endometriosis women with adenomyosis, 40 women with adenomyosis alone, and 41 women with uterine fibroids alone who had undergone laparoscopic hysterectomy between December 2007 and July 2008 at the Women's Hospital, Zhejiang University School of Medicine, China. Of the 42 endometriosis women with adenomyosis, 30 women (mean age = 34.6 years; range = 28–40) complained of dysmenorrhoea and/or pelvic pain, and 12 women (mean age = 35.1 years; range = 29–41) had no pain symptoms. Of the 40 women with adenomyosis alone, 26 women (mean age = 36.9 years; range = 27–45) complained of dysmenorrhoea and/or pelvic pain, and 14 women (mean age = 37.2 years; range = 29–44) had no pain symptoms. Of the 41 women with uterine fibroids alone, 13 women (mean age = 36.6 years; range = 29–46) complained of dysmenorrhoea and/or pelvic pain, and 28 women (mean age = 37.8 years; range = 30–44) had no pain symptoms. The study was approved by The Human Ethics Committees of the Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China. The assessment of pain symptoms for the 30 women with endometriosis alone and the five endometriosis patients with adenomyosis who underwent laparoscopic hysterectomy was graded by using a 100-mm visual analogue scale (VAS), because we could interview with these women and let them to measure VAS pain scores by themselves (7Vercellini P. Pietropaolo G. De Giorgi O. Daguati R. Pasin R. Crosignani P.G. Reproductive performance in infertile women with rectovaginal endometriosis: is surgery worthwhile?.Am J Obstet Gynecol. 2006; 195: 1303-1310Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), whereas the characteristics of pain symptoms for the remaining women were not evaluated systematically because of the retrospective nature of our data for these women. The detailed information such as the stage of menstrual cycle, the definition of the functional layer endometrium, the diagnosis of histopathology, and immunohistochemistry was previously described by Zhang et al. (5Zhang X. Lu B. Huang X. Xu H. Zhou C. Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids.Fertil Steril. 2009 Apr 13; ([Epub ahead of print])Google Scholar). The results showed that PGP9.5-immunoreactive small nerve fibers in the functional layer of the endometrium could only be detected in women with pain symptoms, but not in women without pain symptoms, whether the women had adenomyosis alone, uterine fibroids alone, endometriosis alone, or endometriosis with adenomyosis (Table 1). There were no significant differences of the percentage or density of PGP9.5-positive nerve fibers in the functional layer of the endometrium among endometriosis alone, adenomyosis alone, uterine fibroids alone, and endometriosis with adenomyosis in the women with pain symptoms (χ2 = 2.283, P=.516; H = 4.106, P=.250). Additionally, no neurofilament (NF)-immunoreactive nerve fibers in the functional layer of the endometrium could be detected in women with endometriosis alone, adenomyosis alone, uterine fibroids alone, or endometriosis with adenomyosis.Table 1The density and percentage of PGP9.5-positive nerve fibers in the functional layer of the endometrium in women with endometriosis alone, adenomyosis alone, uterine fibroids alone, and endometriosis with adenomyosis in the women with pain symptoms (per mm2, median [range]).PGP9.5-positive nerve fibersnDensityPercentageaPercentage = patients with PGP9.5-positive nerve fibers/total patients with pain symptoms.Endometriosis with adenomyosis Proliferative220.7 (0∼2.8)59.1% (13/22) Secretory110.5 (0∼1.9)63.6% (7/11) Total330.6 (0∼2.8)60.6% (20/33)Endometriosis alone Proliferative81.3 (0∼2.4)66.7% (6/8) Secretory101.9 (0∼3.0)90.0% (9/10) Total181.5 (0∼3.0)83.3% (15/18)Adenomyosis alone Proliferative150.6 (0∼7.0)53.3%(8/15) Secretory110.3 (0∼2.4)54.5%(6/11) Total260.5 (0∼7.0)53.9% (14/26)Uterine fibroids alone Proliferative80.8 (0∼5.8)75.0% (6/8) Secretory50.7 (0∼2.5)60.0% (3/5) Total130.6 (0∼5.8)69.2% (9/13)a Percentage = patients with PGP9.5-positive nerve fibers/total patients with pain symptoms. Open table in a new tab The mean (±SD) VAS scores in the 18 women with endometriosis alone who had pain symptoms were 60.7 ± 24.8, and had a significant correlation with the density of PGP9.5-immunoreactive nerve fibers in the functional layer of the endometrium (r = .786, P=.00; Pearson Correlation Test). In addition, PGP9.5-immunoreactive nerve fibers in the functional layer of the endometrium could be detected in 66.7% (2/3) of endometriosis patients with adenomyosis undergoing laparoscopic hysterectomy who had pain symptoms. Moreover, there were no statistical differences of PGP9.5-immunoreactive nerve fiber density in the functional layer of the endometrium between the phases of menstrual cycle in women with endometriosis alone, adenomyosis alone, uterine fibroids alone, or endometriosis with adenomyosis for the women with pain symptoms. Several studies by Tokushige et al. (1Al-Jefout M. Andreadis N. Tokushige N. Markham R. Fraser I. A pilot study to evaluate the relative efficacy of endometrial biopsy and full curettage in making a diagnosis of endometriosis by the detection of endometrial nerve fibers.Am J Obstet Gynecol. 2007; 197: 578.e1-578.e4Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 2Tokushige N. Markham R. Russell P. Fraser I.S. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis.Fertil Steril. 2007; 88: 795-803Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 3Tokushige N. Markham R. Russell P. Fraser I.S. High density of small nerve fibers in the functional layer of the endometrium in women with endometriosis.Hum Reprod. 2006; 21: 782-787Crossref PubMed Scopus (163) Google Scholar, 8Tokushige N. Markham R. Russell P. Fraser I.S. Nerve fibers in peritoneal endometriosis.Hum Reprod. 2006; 21: 3001-3007Crossref PubMed Scopus (217) Google Scholar, 9Tokushige N. Markham R. Russell P. Fraser I.S. Effects of hormonal treatment on nerve fibers in endometrium and myometrium in women with endometriosis.Fertil Steril. 2007; 90: 1589-1598Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 10Wang G. Tokushige N. Markham R. Fraser I.S. Rich innervation of deep infiltrating endometriosis.Hum Reprod. 2009 Jan 16; ([Epub ahead of print])Google Scholar) have demonstrated nerve fibers stained with PGP9.5 in the functional layer and basal layer of the endometrium, in myometrium, and in endometriotic lesions in women with endometriosis. However, women with endometriosis in these studies all complained of dysmenorrhoea and a range of related pain symptoms, whereas in women without endometriosis, none of them had pain symptoms. Therefore, it is really unclear whether nerve fibers stained with PGP9.5 in the functional layer endometrium in women with endometriosis are caused by a common symptom of pain or by a disease itself. More recently, a correlation has been demonstrated between nerve fibers in peritonal endometriotic lesions and the severity of pain in women with endometriosis (11Mechsner S. Kaiser A. Kopf A. Gericke C. Ebert A. Bartley J. A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions.Fertil Steril. 2008 Nov 1; ([Epub ahead of print])Google Scholar). Moreover, women with deep infiltrating endometriosis have significantly more nerve fibers in endometriotic lesions than women with superficial peritoneal endometriosis, suggesting a correlation between nerve fibers in endometriotic lesions and the severity of pain (10Wang G. Tokushige N. Markham R. Fraser I.S. Rich innervation of deep infiltrating endometriosis.Hum Reprod. 2009 Jan 16; ([Epub ahead of print])Google Scholar). In this study we found that PGP9.5-immunoreactive nerve fibers in the functional layer of the endometrium were only be present in women with painful endometriosis and/or adenomyosis or uterine fibroids, and showed no statistical differences among endometriosis alone, adenomyosis alone, uterine fibroids alone, and endometriosis with adenomyosis in the women with pain symptoms. Moreover, in women with endometriosis alone who had pain symptoms, PGP9.5-immunoreactive nerve fiber density in the functional layer of the endometrium was statistically correlated with the severity of pain symptoms. Therefore, taken the results from previous studies and our study together, it is implied that nerve fibers in the functional layer endometrium in women with endometriosis are dependent on a common symptom of pain but not on an endometriosis disease itself. In considering the limitation of formalin-fixed and paraffin-embedded tissues, histologic sections of endometria were collected from more recent tissue blocks. Moreover, fresh endometrial tissues sampled from the 30 women with endometriosis alone and the five endometriosis women with adenomyosis were comparatively stained. Consequently, we obtained the same results. It is indicated that histologic sections of formalin-fixed and paraffin-embedded endometrial tissues may not affect our results. In fact, a variety of clinical conditions including endometriosis, adenomyosis, uterine fibroids, and adhesions can cause pelvic pain (12Evans S. Moalem-Taylor G. Tracey D.J. Pain and endometriosis.Pain. 2007; 132: S22-S25Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 13Evans P. Brunsell S. Uterine fibroid tumors: diagnosis and treatment.Am Fam Physician. 2007; 75: 1503-1508PubMed Google Scholar, 14Gupta S. Jose J. Manyonda I. Clinical presentation of fibroids.Best Pract Res Clin Obstet Gynaecol. 2008; 22: 615-626Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 15Ortiz D.D. Chronic pelvic pain in women.Am Fam Physician. 2008; 77: 1535-1542PubMed Google Scholar, 16Yeniel O. Cirpan T. Ulukus M. Ozbal A. Gundem G. Ozsener S. et al.Adenomyosis: prevalence, risk factors, symptoms and clinical findings.Clin Exp Obstet Gynecol. 2007; 34: 163-167PubMed Google Scholar). The relationship between innervation and pain has been demonstrated in many clinical disorders including endometriosis, adenomyosis, uterine fibroids, and adhesions (5Zhang X. Lu B. Huang X. Xu H. Zhou C. Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids.Fertil Steril. 2009 Apr 13; ([Epub ahead of print])Google Scholar, 11Mechsner S. Kaiser A. Kopf A. Gericke C. Ebert A. Bartley J. 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Expression of transforming growth factor beta1 in nerve fibers is related to dysmenorrhea and laparoscopic appearance of endometriotic implants.Fertil Steril. 2003; 80: 1131-1136Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). It is suggested that neural reinnervation of organs is a common phenomenon because of previous denervation in different gynecologic conditions including chronic pelvic pain, menstrual problems, irritable bladder syndrome, rectal hypersensitivity, dyspareunia, vulvodynia, and in other medically unexplained pain conditions such as irritable bowel, interstitial cystitis, and fibromyalgia (4Quinn M.J. Endometrial nerve fiber proliferation in "endometriosis".Am J Obstet Gynecol. 2008; 199: e13-e14Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 12Evans S. Moalem-Taylor G. Tracey D.J. Pain and endometriosis.Pain. 2007; 132: S22-S25Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 18Mechsner S. Schwarz J. Thode J. Loddenkemper C. Salomon D.S. Ebert A.D. Growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions.Fertil Steril. 2007; 88: 581-587Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 24Atwal G. du Plessis D. Armstrong G. Slade R. Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis.Am J Obstet Gynecol. 2005; 193: 1650-1655Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Moreover, regional uterine denervation is also associated with some forms of adenomyosis and leiomyomas, respectively (4Quinn M.J. Endometrial nerve fiber proliferation in "endometriosis".Am J Obstet Gynecol. 2008; 199: e13-e14Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 25Quinn M. Uterine innervation in adenomyosis.J Obstet Gynaecol. 2007; 27: 287-291Crossref PubMed Scopus (42) Google Scholar, 26Quinn M. Uterine innervation in fibroids: a qualitative study.J Obstet Gynaecol. 2007; 27: 489-492Crossref PubMed Scopus (19) Google Scholar). Therefore, it is believed that the innervation of the functional layer endometrium is most likely to be a "common symptom" of many gynecologic conditions. In conclusion, our study demonstrated PGP9.5 but not NF-immunoactive nerve fibers in the functional layer endometrium in women with painful endometriosis and/or adenomyosis or uterine fibroids, suggesting a role of PGP9.5-immunoactive nerve fibers in the functional layer endometrium playing in the mechanisms of pain generation in these disorders. This study was supported by National Natural Science Foundation of China (NSFC30872754) and Zhejiang Provincial Natural Science Foundation of China (Y2080123).
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