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Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO) involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.

Purpose of Investigation: The aim of this study was to find whether nerve-sparing radical hysterectomy resulted in a lower amount of nerves in the removed parametrial tissue., Methods: Histological specimens from nerve-sparing radical hysterectomy (28 cases) were compared with those obtained after classic radical hysterectomy (26 cases). Width of the parametria and vaginal cuff were measured. Using a point counting technique, nerve areal density was determined in cross sections of resected parametria at 0.5 cm (A), 1 cm (B), 1.5 cm (C) from the cervix., Results: The width of the resected parametria was smaller in the study group (right side p < 0.013; left side; p < 0.011). The nerve areal density in the lateral part of the right parametrium was lower in the study group (p < 0.01) (Student's t-test). CCONCLUSION: Modified radical hysterectomy is less radical and is nerve-sparing.

During pregnancy the mammalian uterine circulation undergoes significant expansive remodelling necessary for normal pregnancy outcome. The underlying mechanisms are poorly defined. The goal of this study was to test the hypothesis that myometrial stretch actively stimulates uterine vascular remodelling by developing a new surgical approach to induce unilateral uterine distension in non-pregnant rats. Three weeks after surgery, which consisted of an infusion of medical-grade silicone into the uterine lumen, main and mesometrial uterine artery and vein length, diameter and distensibility were recorded. Radial artery diameter, distensibility and vascular smooth muscle mitotic rate (Ki67 staining) were also measured. Unilateral uterine distension resulted in significant increases in the length of main uterine artery and vein and mesometrial segments but had no effect on vessel diameter or distensibility. In contrast, there were significant increases in the diameter of the radial arteries associated with the distended uterus. These changes were accompanied by reduced arterial distensibility and increased vascular muscle hyperplasia. In summary, this is the first report to show that myometrial stretch is a sufficient stimulus to induce significant remodelling of uterine vessels in non-pregnant rats. Moreover, the results indicate differential regulation of these growth processes as a function of vessel size and type.

Difficult intrapartum episodes and persistent straining during defecation cause injuries to uterine nerves and uterosacral ligaments. Injuries to uterine nerves (denervation) result in loss of fundocervical polarity, uterotubal dysmotility and retrograde menstruation. Ectopic endometrium, delivered by retrograde menstruation, adheres to injuries to uterosacral ligaments and peritoneal surfaces. Difficult vaginal deliveries result in laparoscopic appearances of asymmetry of uterosacral ligaments with, or without, ectopic endometrium. Straining during defaecation causes the "classic" appearances of nulliparous endometriosis including hypertrophy of the uterosacral ligaments often with large volumes of ectopic endometrium. Laparoscopic appearances depend on the site, nature, extent, and timing of tissue injury, as well as the presence of available endometrium. Tissue repair, including reinnervation in the uterine isthmus, cervix, vagina and uterosacral ligaments, contributes to chronic pelvic pain, dysmenorrhea, dyspareunia and subfertility some time after the primary injuries.

Current evidence indicates that rises in systemic levels of estrogen create in the uterus an inhibitory environment for sympathetic nerves. However, molecular insights of these changes are far from complete. We evaluated if semaphorin 3F mRNA, a sympathetic nerve repellent, was produced by the rat uterus and if its expression was modulated by estrogen. We also analyzed whether uterine nerves express the semaphorin 3F binding receptor, neuropilin-2. Uterine levels of semaphorin 3F mRNA were measured using real time reverse transcriptase-polymerase chain reaction in prepubertal rat controls and following chronic estrogen treatment. Localization of semaphorin 3F transcripts was determined by in situ hybridization and the expression of neuropilin-2 was assessed by immunohistochemistry. These studies showed that: (1) chronic estrogen treatment led to a 5-fold induction of semaphorin 3F mRNA in the immature uterus; (2) estrogen provoked a tissue-specific induction of semaphorin 3F which was particularly localized in the connective tissue that borders muscle bundles and surrounds intrauterine blood vessels; (3) two major cell-types were recognized in the areas where transcripts were concentrated, fibroblast-like cells and infiltrating eosinophil leukocytes; and (4) some delicate nerve terminal profiles present in the estrogenized uterus were immunoreactive for neuropilin-2. Temporal and spatial expression patterns of semaphorin 3F/neuropilin-2 are consistent with a possible role of this guidance cue in the remodeling of uterine sympathetic innervation by estrogen. Though correlative in its nature, these data support a model whereby semaphorin 3F, in combination with other inhibitory molecules, converts the estrogenized myometrium to an inhospitable environment for sympathetic nerves., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The innervation of the nonpregnant rat uterus has been studied in histological sections, which contain only small samples of nerves and are unlikely to afford a complete picture of uterine innervation. Here we used whole-mount preparations of entire full-thickness uterine horns from nonpregnant rats in estrus to visualize autonomic or sensory nerves with peroxidase immunohistochemistry. Immunoreactivity was studied for tyrosine hydroxylase (TH)-labeled sympathetic nerves; vesicular acetylcholine transporter (VAChT), parasympathetic nerves; and substance P (SP) and calcitonin gene-related peptide (CGRP), sensory nerves. Neuropeptide Y (NPY) and nitric oxide synthase (NOS) identified more than one of these functionally distinct nerve types. Axons of all neurochemical classes entered the uterus at the mesometrium and innervated the uterine smooth muscle. The linea uteri, a dense band of longitudinal muscle opposite the mesometrium, contained more TH-, NPY-, CGRP-, and VAChT-immunoreactive axons than the remaining smooth muscle. Axons immunoreactive for NPY, SP, NOS, and VAChT formed a plexus near the circular muscle-endometrium interface. Rare TH- and NPY-immunoreactive axons and occasional CGRP-immunoreactive axons occurred close to uterine glands. Blood vessels had dense perivascular plexuses of TH- and NPY-containing axons and less dense NOS-, SP-, CGRP-, and VAChT-positive plexuses. The circular muscle plexus and glands were absent opposite the mesometrium. Uterine arterioles formed an interconnected network throughout the uterus. This article provides the first comprehensive description of the autonomic and sensory innervation of the nonpregnant rat uterus and will be a foundation for future studies on changes in uterine innervation caused by normal physiological or pathophysiological challenges., (Copyright © 2010 Wiley-Liss, Inc.)

The authors studied the presence of substance P (SP) and vasoactive intestinal polypeptide (VIP) and their related fibers in the lower uterine segment (LUS) in 133 women undergoing cesarean sections (CS) during active labor. These were divided into 2 groups: women undergoing repeat or first CSs. Specimens were collected from the LUS and were evaluated by light microscopy and by immunohistochemistry, for the morphometrical quantification of the SP and VIP fibers in the LUS. The SP amount was higher in the post-CS scar, while the VIP amount decreased: nerve fibers contained an SP amount of up to 13 ± 2.6C.U., while nerve fibers contained a VIP amount of up to 7 ± 1.9 C.U. The SP amount counts 10 ± 1.5% of the total Bodian fibers, and the ratio of the VIP is 10 ± 1.8% of their total amount. In normal conditions only 6.61 C.U. of the Bodian surface is occupied by SP related nerve fibers in contrast to 6.63 C.U. of the total surface by VIP; the amount of SP increased up to 13 ± 2.6C.U., while it decreased in the LUS previous scars. The SP levels are higher in repeat CS, while the VIP levels are reduced in the LUS. The increase of SP is probably linked to the attempt to achieve cervical ripening in a post-CS LUS, with the possible consequences of dystocia during vaginal birth after CS. Nevertheless, the decrease of VIP probably affects the relaxation of the internal uterine orifice, compromising the LUS formation and cervical ripening., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: There have been conflicting results in randomized trials of the effects of laparoscopic uterosacral nerve ablation (LUNA) in chronic pelvic pain. Our objective was to perform a meta-analysis using individual patient data (IPD) to provide the most comprehensive and reliable assessment of the effectiveness of LUNA., Methods: Electronic searches were conducted in the Medline, Embase, PsycInfo and Cochrane Library databases from database inception to August 2009. The reference lists of known relevant papers were searched for any further articles. Randomized trials comparing LUNA with no additional intervention were selected and authors contacted for IPD. Raw data were available from 862 women randomized into five trials. Pain scores were calibrated to a 10-point scale and were analysed using a multilevel model allowing for repeated measures., Results: There was no significant difference between LUNA and No LUNA for the worst pain recorded over a 12 month time period (mean difference 0.25 points in favour of No LUNA on a 0-10 point scale, 95% confidence interval: -0.08 to 0.58; P = 0.1)., Conclusions: LUNA does not result in improved chronic pelvic pain.

Purpose of Review: The present review highlights recent findings focusing on effects on the cervical innervation exerted by term pregnancy and labour., Recent Findings: The corpus uteri is almost denervated in term pregnancy, as demonstrated in both humans and rodents, whereas the cervical innervation remains dense throughout pregnancy and labour. In rats, fewer connections between sensory subdivisions in spinal cord segments and the cervix have been observed in late pregnancy as compared with the nonpregnant state. In term pregnancy an increased excitability of mechanosensitive afferents innervating the cervix has been demonstrated. The reasons for these seemingly contradictory findings may be clarified in further studies. Transient receptor potential vanilloid receptor, a key molecule in nociception, has been identified in the human cervix uteri in the nonpregnant state and during pregnancy and labour as opposed to the corpus, in which transient receptor potential vanilloid receptor disappears during pregnancy. These findings add evidence to the hypothesis that the uterine cervix is the main site from where labour pain propagates., Summary: The conservation of the cervical innervation in term pregnancy and labour, in contrast to the corpus, and the large number of mediators involved in cervical ripening clearly indicate that the cervix plays a crucial role in pregnancy maintenance, labour initiation, labour pain and parturition.

In order to evaluate the contribution of substrate-bound factors to the extent and patterning of the sympathetic innervation of rat uterus following estrogen treatment, superior cervical ganglion explants from neonatal and adult ovariectomized rats were cultured on tissue sections of fresh frozen uterus from adult ovariectomized rats treated with estrogen or a vehicle. The main findings were: (1) neurite growth was greatly influenced by histological features of the underlying section; (2) on myometrial sections, neurites followed the orientation of the main axis of the longitudinally sectioned muscle cells; (3) neurites showed limited growth on transversally sectioned smooth muscle; (4) neuritic patterning was unaffected by a reduction in migrating ganglionic non-neuronal cells; (5) neurite outgrowth, but not non-neural cell migration, was markedly reduced on myometrial sections from rats treated with estrogen. These results suggest that adult myometrium continues to provide signals allowing the organotypic patterning and growth of sympathetic axons, that estrogen treatment modifies myometrial substrate properties so that it is less supportive for sympathetic neurite growth, and that adult sympathetic neurons retain their ability to recognize substrate-bound cues present in the myometrium. On endometrial sections, neurites formed radially symmetric halos, which were reduced in size on estrogen-treated endometrial substrates. Thus, changes in the neuritogenic capacity of the uterus underlie plasticity in uterine sympathetic nerves, and alterations in substrate-bound factors contribute to the diminished receptivity of the estrogenized uterus to its sympathetic innervation.

Objective: To investigate the relationship between the distribution of nerve fibers in multiple endometriosis lesions and pelvic pain., Methods: From Sept. 2007 to Sept. 2008, 120 endometriosis patients treated in Peking Union Hospital were enrolled in this study, which including 19 cases with stage I, 29 cases with stage II, 44 cases with stage III and 28 cases with stage IV. The pain symptom was evaluated by visual analogue scales (VAS) score and nerve fibers in multiple endometriosis lesions were detected by immunohistochemical staining., Results: The number of nerve fibers in multiple endometriosis lesions were (29.74+/-17.33)/mm2 in uterosacral ligament, (24.53+/-13.34)/mm2 in vaginal septum, (17.09+/-10.09)/mm2 in uterus rectum crux, (6.77+/-4.21)/mm2 in peritoneal endometriosis lesions, (0.07+/-0.25)/mm2 in endometriosis ovarian cyst wall. The number of nerve fibers in uterosacral ligament was mostly correlated with the degree of pain (r=0.56). The nerve fibers of uterus rectum crux and vaginal septum were correlated with defecation pain (r=0.58 and 0.41) and dyspareunia (r=0.82 and 0.67), which were significantly higher than those in endometriosis leision in peritoneum and ovary. There was no significant different number of nerve fibers among different stage disease (P>0.05)., Conclusion: There was significantly different distribution of nerve fibers in multiple endometriosis lesions, which was correlated with dysmenorrhea, anus pain, dyspareunia and chronic pelvic pain, not with clinical staging.

To explore the potential mechanism of how uterine innervations would affect the uterine mast cell (MC) population and functions during the periimplantation. We herein first examined the consequence of uterine neurectomy on embryo implantation events. We observed that amputation of autonomic nerves innervating the uterus led to on-time implantation failure in rats. Exploiting MC culture and ELISA approaches, we then further analyzed the effect of neurectomy on cellular histamine levels and its release from uterine MCs, to elucidate the relation of the autonomic nerves and local cellular immunity in the uterine during early pregnancy. We observed that disconnection of autonomic nerve innervation significantly increased the population of uterine MCs. Most interestingly, these increased number of uterine MCs in neuroectomized rats contained a much reduced cellular level of histamine. Our subsequent challenge experiments revealed that uterine MCs in nerve amputated rats exhibited enhanced histamine releasing rate in response to substance P and antiIgE, suggesting loss of nerve innervation in the uterus not only increases the population of uterine MCs, but also facilitates the release of histamine from MCs, thus subsequently interfere with the normal implantation process. Collectively, our findings provide a new line of evidence supporting the concept that immune-neuro-endocrine network plays important role during pregnancy establishment and maintenance.

Objective: To investigate the pathogenesis of endometriotic pain., Design: Retrospective nonrandomized immunohistochemical study., Setting: A university hospital, Department of Gynecology., Patient(s): Twenty human endometriotic specimens were selected from different lesions including ovarian endometrioma, peritoneal lesion, and deep infiltrating lesion. Premenopausal women with histologically diagnosed endometriosis were selected (mean age 39 years; range, 25-53 years). The chief complaint was dysmenorrhea, dyschezia, and dyspareunia. A rat endometriosis model was induced in 10 SLC-Sprague-Dawley rats (8 weeks old) by surgical autotransplantation of the uterus., Intervention(s): Immunohistochemical staining of endometriotic specimens for alpha-smooth muscle actin (ASMA), neural cell adhesion molecule (NCAM), and nerve growth factor (NGF) expression., Main Outcome Measure(s): Comparison of the immunoreactive staining of ASMA, NCAM, and NGF expression in human endometriosis and a rat endometriosis model., Result(s): Morphological analysis revealed thick interstitium in both human and rat endometriotic lesions. The major components of fibrotic interstitium are smooth muscle cells, stained by anti-ASMA antibody, and nerve cells, stained by anti-NCAM antibody. Inflammatory cells are also present (e.g., macrophages and lymphocytes) as revealed by anti-NGF antibody staining., Conclusion(s): These results suggest that the contraction of smooth muscle cells and the hyperalgia derived from innervation in the interstitial area is related to pain in endometriosis.

The denervation-reinnervation view proposes that retrograde menstruation results from loss of normal, fundocervical polarity caused by injuries to uterine nerves. Injuries may be sporadic (following vaginal delivery) or recurrent (after persistent straining during defaecation) creating very different appearances at laparoscopy. Clinical symptoms of pelvic pain, menstrual problems, dyspareunia, and dysmenorrhoea result from aberrant reinnervation that may occur with, or without deposits of pelvic endometriosis. Endometrium, delivered by retrograde menstruation, adheres to any injured tissues in the lower pelvis. Classical 'endometriosis' is largely an epiphenomenon to underlying processes of denervation and reinnervation.

Context: Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain., Objective: To assess the effectiveness of LUNA in patients with chronic pelvic pain., Design, Setting, and Participants: Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years., Intervention: Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation., Main Outcome Measures: The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS)., Results: After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life., Conclusion: Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation., Trial Registration: controlled-trials.com Identifier: ISRCTN41196151.

Females of many animal species behave very differently before and after mating. In Drosophila melanogaster, changes in female behavior upon mating are triggered by the sex peptide (SP), a small peptide present in the male's seminal fluid. SP activates a specific receptor, the sex peptide receptor (SPR), which is broadly expressed in the female reproductive tract and nervous system. Here, we pinpoint the action of SPR to a small subset of internal sensory neurons that innervate the female uterus and oviduct. These neurons express both fruitless (fru), a marker for neurons likely to have sex-specific functions, and pickpocket (ppk), a marker for proprioceptive neurons. We show that SPR expression in these fru+ ppk+ neurons is both necessary and sufficient for behavioral changes induced by mating. These neurons project to regions of the central nervous system that have been implicated in the control of reproductive behaviors in Drosophila and other insects.

Spinal cord-mediated cross-organ sensitization between the uterus and the lower urinary tract may underlie the high concurrence of obstetrical/gynecological inflammation and chronic pelvic pain syndrome characterized by urogenital pain. However, the neural pathway and the neurotransmitters involved are still unknown. We tested the hypothesis that the excitation of capsaicin-sensitive primary afferent fibers arising from the uterus through the stimulation of transient receptor potential vanilloid 1 (TRPV1) induces cross-organ sensitization on the pelvic-urethra reflex activity. Capsaicin (1-1,000 microM, 0.05 ml) was instilled into the uterus to induce cross-organ reflex sensitization. Activation of capsaicin-sensitive primary afferent fibers by capsaicin instillation into the uterine horn sensitized the pelvic-urethra reflex activity that was reversed by an intrauterine pretreatment with capsaizepine, a TRPV1-selective antagonist. Intrathecal injection of AP5, a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, and Co-101244, an NMDA NR2B-selective antagonist, both abolished the cross-organ reflex sensitization caused by capsaicin instillation. These results demonstrated that TRPV1 plays a crucial role in contributing to the capsaicin-sensitive primary afferent fibers mediating the glutamatergic NMDA-dependent cross-organ sensitization between the uterus and the lower urinary tract when there is a tissue injury.

The radical hysterectomy is often associated with severe bladder dysfunction and colorectal motility disorders. These issues may arise as a result of damage incurred to the motor and sensory autonomic nerve supply, both of sympathetic and parasympathetic origin, that innervate the uterus, vagina, urinary bladder, and rectum. In this article, we demonstrate a nerve-sparing radical hysterectomy using illustrations and step-by-step instructions.

Unlabelled: Endometriosis is a disease of high prevalence and enigmatic origin. One aspect not yet clarified is the relationship between endometriosis and nerve tissue., Objective: To evaluate, by immunohistochemistry, the presence of sympathetic and parasympathetic nerve fibers in the uterosacral ligament and adjacent connective tissue in women with deep pelvic endometriosis and women without endometriosis., Design: Cross-sectional study (Canadian Task Force II)., Setting: University Hospital. Obstetrics and Gynecology Department, Santa Casa Medical School, São Paulo, Brazil., Methodology: We selected 49 patients, 20 of them with deep endometriosis in the uterosacral ligament and 29 patients without endometriosis. Secondary antibodies to NSE (pan-neuronal marker), NPY (that identifies sympathetic nerve fibers), and VIP (that identifies parasympathetic nerve fibers) were used for the immunohistochemistry analyses., Results: The immunohistochemical staining by the NSE antibody was positive in 40% of cases of women with endometriosis and in 20.7% of patients without endometriosis (non-significant). The immunohistochemical staining by the NPY antibody was positive in 60% of patients with endometriosis and in 20.7% of the control group (p=0.005), while staining by the VIP antibody was 60% in patients with endometriosis and 13.8% in patients without endometriosis (p=0.001)., Conclusion: Immunoexpression of NPY (sympathetic fibers) and VIP (parasympathetic fibers) is higher in women with deep pelvic endometriosis than in women without endometriosis.

This minireview reports current hypotheses concerning the remodeling of sympathetic innervation in rodent and human uterus during the estrous cycle and gestation. Neural modulation in this organ is related to sexual hormone concentrations, and a reduction in nerve density is observed when estrogen levels are high during the estrous cycle. Estrogen receptor alpha is considered to be the major receptor mediating the action of estrogen. In the uterus, the expression of neurotrophins, such as nerve growth factor, which are involved in the survival and growth of nerve fibers, changes in response to steroid levels. Despite much research, further studies are necessary to clarify various aspects of nerve growth control under diverse physiological conditions. These studies could be of importance, since alterations of the biological mechanisms of uterus innervation may play significant roles in various pathologies, such as infertility and spontaneous abortion.

In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. One of the possible explanations for this phenomenon is viscerovisceral cross-sensitization, in which increased nociceptive input from an inflamed pelvic organ sensitizes neurons that receive convergent input to the same dorsal root ganglion (DRG) from an unaffected visceral organ. Nociception induces up-regulation of cellular mechanisms such as phosphorylated extracellular signal-regulated kinase (pERK) and substance P (SP), neurotransmitters associated with induced pain sensation. The purpose of this study was to determine, in a rodent model, whether uterine inflammation increased the number of pERK- and SP-positive neurons that received input from both the uterus and the colon. Cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and into the uterus. Ganglia were harvested for fluorescent microscopy to identify positively stained neurons. Approximately 6% of neurons were colon specific and 10% uterus specific. Among these uterus- or colon-specific neurons, up to 3-5% of DRG neurons in the lumbosacral neurons (L1-S3 levels) received input from both visceral organs. Uterine inflammation increased the number of pERK- and SP-immunoreactive DRG neurons innervating specifically colon, or innervating specifically uterus, and those innervating both organs. These results suggest that a localized inflammation activates primary visceral afferents, regardless of whether they innervate the affected organ. This visceral sensory integration in the DRG may underlie the observed comorbidity of female pelvic pain syndromes., ((c) 2008 Wiley-Liss, Inc.)

The objectives of the study were to present a new approach for nerve-sparing radical hysterectomy (NSRH) with the assistance of magnifying lenses and to describe the differences in autonomic nerve plexus trauma between NSRH type III and conventional radical hysterectomy (RH) types II and III with the aid of immunohistochemistry. Eighteen women with FIGO stage IB(1)-IB(2) cervical cancer underwent loupes-assisted NSRH (n = 8), RH type II (n = 6), and RH type III (n = 4). Biopsies were taken intraoperatively from uterosacral ligament (USL) and cardinal ligament (CL), as well as from anterior vaginal wall (AVW) and posterior vaginal wall (PVW). Immunohistochemistry was approached with the use of S-100 protein, a general nerve marker. The percentage area of immunoreactivity (PAI) was used as an objective quantitative measure of nerve fibers within the ligaments. The PAI was greater in RH-III biopsies from both USL and CL (P < 0.001) when compared with RH-II and NSRH biopsies. For AVW and PVW, PAI differences were not statistically significant (AVW, P = 0.119; PVW, P = 0.067). Uterine-supporting ligaments represent a major pathway for autonomic nerves to the pelvic organs. As significantly more autonomic nerves are transected during the division of the uterine-supporting ligaments in RH type III, a more careful approach in the dissection of the ligaments through nerve-preserving techniques seems to be necessary in order to prevent iatrogenic intraoperative injury of the pelvic plexus and reduce or prevent postoperative complications.

Dynamic responses of uterine sympathetic nerves to changes in the circulating levels of sex hormones represent one of the most remarkable examples of physiological plasticity in the adult autonomic nervous system. The density of uterine sympathetic nerves is markedly and irreversibly reduced following puberty, and shows phases of degeneration and regeneration during the natural oestrous cycle. Even more remarkable, uterine sympathetic nerves degenerate during normal pregnancy and regenerate following delivery. Plasticity in uterine sympathetic nerves was initially interpreted as a selective effect of sex hormones on the system of paracervical short adrenergic neurons supplying the uterus. In the last decade, the alternative explanation that sex hormones might alter the ability of the uterine tissue to support its innervation began to be explored and current evidence indicates that oestrogen and pregnancy elicit changes in the neuritogenic properties of the target uterine tissue. In addition, there are indications that sex hormones may also affect the receptivity of uterine-related sympathetic neurons to target-derived signals. Although the nature of these signals is still fragmentary, there is evidence for the contribution of a range of molecules, including neurotrophins, pro-neurotrophins and chemorepulsive signals of the semaphorin family. This review summarizes some general features of plasticity in uterine sympathetic nerves and highlights recent investigations of the cellular and molecular mechanisms underlying this dramatic model of natural plasticity.

The introduction of minimally invasive techniques over recent years has led to the resurgence of pelvic denervation procedures such as presacral neurectomy and uterine nerve ablation being performed for women with dysmenorrhea and pelvic pain. Women who have failed medical therapy with persistent and debilitating symptoms may certainly benefit from these procedures. However, presacral neurectomy and uterine nerve ablation are distinct procedures that require appropriate patient selection in order to optimize pain relief. Whereas presacral neurectomy may be effective for both primary dysmenorrhea and endometriosis-related pelvic pain, the role of uterine nerve ablation should be reserved for patients with primary dysmenorrhea only, as evidenced by several randomized trials.

Most neurons that regulate motility and blood flow in female pelvic organs are located within pelvic (paracervical) ganglia. In this study we investigated the anatomical and physiological properties of neurons within mouse (C57/Bl/6) paracervical ganglia. Most neurons showed immunoreactivity for choline acetyl transferase (CHAT) and were presumably cholinergic. Few neurons (approximately 5%) were tyrosine hydroxylase (TH) positive. Immunohistochemical labelling for microtubule associated protein 2 showed most neurons had small somata (cross sectional area approximately 300 microm(2)) and lacked dendrites. Action potential (AP) discharge characteristics, determined by depolarising current step injection, revealed most neurons (70%) adapted rapidly to depolarising current injection and were classified as "phasic". The remaining neurons discharged APs throughout the current step and were classified as "tonic". Membrane properties and current-voltage relationships were similar in phasic and tonic neurons, however the afterhyperpolarisation was significantly smaller in tonic neurons. Stimulation of preganglionic axons usually evoked a single strong preganglionic input (21/27 and 9/10 for pelvic and hypogastric nerves, respectively). In 19 preparations where we tested for inputs from both nerves pelvic inputs predominated (23/45 neurons) and inputs via the hypogastric nerve were rarely observed (3/45 neurons). Together, our data indicate that most neurons within mouse paracervical ganglia are cholinergic and parasympathetic. As there is little anatomical or functional evidence for integration of preganglionic inputs we propose that the role of paracervical neurons is restricted to one of spatial amplification or filtering of preganglionic inputs.

In women, clinical studies suggest that functional pain syndromes such as irritable bowel syndrome, interstitial cystitis, and fibromyalgia, are co-morbid with endometriosis, chronic pelvic pain, and others diseases. One of the possible explanations for this phenomenon is visceral cross-sensitization in which increased nociceptive input from inflamed reproductive system organs sensitize neurons that receive convergent input from an unaffected visceral organ to the same dorsal root ganglion (DRG). The purpose of this study was to determine whether primary sensory neurons that innervate both visceral organs--the uterus and the colon--express nociceptive ATP-sensitive purinergic (P2X3) and capsaicin-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes micro-injected into the colon/rectum and uterus of rats. Ganglia were harvested, cryo-protected, and cut in 20-microm slices for fluorescent microscopy to identify positively stained cells. Up to 5% neurons were colon-specific or uterus-specific, and 10%-15% of labeled DRG neurons innervate both viscera in the lumbosacral neurons (L1-S3 levels). We found that viscerally labeled DRGs express nociceptive P2X3 and TRPV1 receptors. Our results suggest a novel form of visceral sensory integration in the DRG that may underlie co-morbidity of many functional pain syndromes.

Background: Cervical ripening is a prerequisite for a normal obstetrical outcome. This process, including labor, is a painful event that shares features with inflammatory reactions where peripheral nociceptive pathways are involved. The capsaicin and heat receptor TRPV1 is a key molecule in sensory nerves involved in peripheral nociception, but little is known regarding its role in the pregnant uterus. Therefore, the aim of this study was to investigate human corpus and cervix uteri during pregnancy and labor and non-pregnant controls for the presence of TRPV1., Methods: We have investigated human uterine corpus and cervix biopsies at term pregnancy and parturition. Biopsies were taken from the upper edge of the hysterotomy during caesarean section at term (n = 8), in labor (n = 8) and from the corresponding area in the non-pregnant uterus after hysterectomy (n = 8). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial frozen sections were examined immunohistochemically using specific antibodies to TRPV1 and nerve markers (neurofilaments/peripherin)., Results: In cervix uteri, TRPV1-immunoreactive fibers were scattered throughout the stroma and around blood vessels, and appeared more frequent in the sub-epithelium. Counts of TRPV1-immunoreactive nerve fibers were not significantly different between the three groups. In contrast, few TRPV1-immunoreactive fibers were found in nerve fascicles in the non-pregnant corpus, and none in the pregnant corpus., Conclusion: In this study, TRPV1 innervation in human uterus during pregnancy and labor is shown for the first time. During pregnancy and labor there was an almost complete disappearance of TRPV1 positive nerve fibers in the corpus. However, cervical innervation remained throughout pregnancy and labor. The difference in TRPV1 innervation between the corpus and the cervix is thus very marked. Our data suggest that TRPV1 may be involved in pain mechanisms associated with cervical ripening and labor. Furthermore, these data support the concept that cervix uteri may be the major site from which labor pain emanates. Our findings also support the possibility of developing alternative approaches to treat labor pain.

The aim of the study was to review the literature concerning nerve sparing radical hysterectomy (NSRH). The data about anatomical and physiological background of this operation, its history, technique and perspectives has been presented. In conclusion it has been estimated that the technique is new and its oncological efficiency is not yet fully established; it requires special anatomical knowledge and new instruments.

The aim of this study is to describe the histologic architecture of the tissues corresponding to the surgically developed connective tissue bundle commonly referred to as the posterior leaf of the vesico-uterine ligament (VUL), and to examine distribution of ganglion cells. Serial macroscopic slices, each 15-20 mm in thickness, were made from eight specimens (obtained from six female elderly cadavers). In these macroslices, the location of the deep uterine vein was used to identify the deep leaf of the VUL. The specimens were trimmed and semi-serial histologic sections in thickness were prepared at 1 mm intervals. Vesical veins and the associated nerve elements were enclosed by fascia and formed a common pedicle. The base of the pedicle contained the deep uterine vein trunk. The fascia encircling the pedicle varied in thickness and connective intensity between specimens. This vesical neurovascular bundle contained abundant ganglion cells. On average, 48.0% of the ganglion cells along the vesical tributaries of the deep uterine vein were located on the medial or vaginal side of the veins, 19.2% were located between veins, 13.0% on the lateral side of the veins, and 19.8% on the dorsal side. The interindividual variability was greatest on the dorsal side of vesical veins and ranged 11-202 cells. We conclude that in order to achieve maximal preservation of the ganglion cells during the surgical dissection of the posterior leaf of the VUL, care must be taken when the medial or vesical aspect of the ligament is separated. The standard nerve-sparing radical hysterectomy should be modified to reflect differences in the distribution of ganglion cells and in connective intensity between ganglions and veins.

Uterus sympathetic nervous apparatus in various phases of sexual cycle in rats was studied with the microspectral fluorescent method. The main part of nervous fibers in the form of perivascular plexus and terminals deviating from them are localized in myometrium. We suppose presence of reserve ("silent") nervous fibers in uterus which explains the inconstancy of their revealing in the organ. Catecholamines and serotonin are identified in varicose enlargements and intervaricose parts of nervous fibers by the way of microspectrofluorometry. Their concentration in probing places is characterized by high degree of linear correlation at all stages of sexual cycle. Maximal concentration of bioamines in most structural elements of uterus sympathetic nervous apparatus in detected in late diestrus. Stages of early and late estrus and proestrus are characterized by low levels of monoamines in adrenergic fibers. A number of reliable differences between bioamines saturation and spatial distribution density of nervous fibers in the neck and body of the womb are revealed.

Background: Currently, there are a number of clinical trials, but no international collaboration for collating research on effectiveness of laparoscopic uterosacral nerve ablation (LUNA) for alleviating chronic pelvic pain., Objective: Meta-analysis was used by collecting individual patient data (IPD) from the existing trials, to provide a comprehensive assessment of the effectiveness of LUNA that will be generalisable in various clinical contexts., Methods: IPD will be sought and collected from all relevant (both already finished and continuing) randomised trials identified through previous systematic reviews. After obtaining raw data and cleaning the database, analysis will be of all patients ever randomised based on the intention-to-treat principle using endpoints measured at 12 months following randomisation., Proposal: We will update searches, contact all authors, obtain data in whatever form it can be provided, build a single database, produce results for individual studies, have them verified by original authors, explore of any heterogeneity and reasons behind it and finally pool all raw data in to a meta-analysis using appropriate statistical methods. The project will test the effectiveness of LUNA for women with chronic pelvic pain. It will also motivate collaborating primary investigators to undertake new primary studies to corroborate or improve upon the conclusions derived from the retrospective analysis.

Estrogen and glucocorticoids are known to evoke opposing effects on the uterus. We analyzed the effects of dexamethasone (DEX) on uterine sympathetic denervation elicited by short- and long-term exposure to estrogen of intact prepubertal rats. We also studied the effects of DEX on the physiological degeneration of uterine sympathetic nerves at term pregnancy. Changes in innervation were assessed quantitatively by using computer-assisted methods on uterine cryostat tissue sections stained for tyrosine hydroxylase. At 24 h following treatment of prepubertal rats (25 days of age) with 1 microg or 2.5 microg estrogen, marked increases in uterine size and reductions in the percentage nerve area were observed. Co-administration of DEX (4 mg/kg) attenuated both these short-term estrogen-induced effects. Treatment of 19-day-old rats with a single dose of 25 mug estrogen provoked, at 26 days of age, a 54% reduction in the total nerve area. This reduction was abolished by the co-administration of nine doses of DEX (0.5 mg/kg) at 18-26 days of age. Treatment of rats with the same regime of DEX alone increased the total nerve area by 46% of the control values. Studies of control pregnant rats revealed the unexpected presence of intrauterine nerve fibers at term. Treatment of pregnant rats with six doses of DEX (4 mg/kg) at 16-21 days of age had no effects on the density of uterine sympathetic nerves. These results suggest that DEX has growth-promoting effects on immature uterine sympathetic nerves and may antagonize the degenerative effects elicited by long-term exposure to estrogen.

Pregnancy-induced diabetes mellitus poses one of the greatest challenges in obstetrical practice. The direct action of diabetes on the myometrial adrenergic functions has not been completely characterized. Accordingly, the present study relates to the impact of experimentally induced diabetes on the presynaptic functions of the rat uterus in relation to gestational age. Experiments were carried out on non-pregnant, early-pregnant (day 7), middle-pregnant (day 14) and late-pregnant (day 21) animals. Diabetes was induced with streptozotocin (60 mg/kg, i.v.) in virgin female or early-pregnant animals (on day 2 for the day 7 experiments and on day 5 for the experiments on the middle and late-pregnant animals). Myometrial samples were utilized for superfusion experiments. After saturation, [3H]noradrenaline perfusate fractions were collected and electric field stimulation was applied to determine the amount of transmitter liberated. Additionally, the total uptake capacity of each sample was assayed. Experimental diabetes decreases the transmitter uptake capacity both in virgin rats and at all stages of pregnancy. In early pregnancy (on day 7), this limitation in uptake is obvious as early as 5 days after the induction of diabetes. In non-pregnant animals, the electrically stimulated transmitter release is inhibited substantially, a similar decrease being observed only at mid-pregnancy (day 14). The present superfusion study proves that experimental diabetes depresses the presynaptic adrenergic functions (both the transmitter uptake and the stimulated release) in the myometrium of the rat. Since the effect of diabetes on the uptake capacity can be detected earlier than for generally accepted markers of peripheral neuropathies, superfusion can be suggested as a sensitive and reliable approach for investigations of hyperglycaemia-related functional deteriorations. We speculate that diabetes-induced functional deterioration of the adrenergic nerves could partially explain the anomalies of the reproductive functions found in diabetic patients if a similar mechanism is operative in humans.

We examined an aqueous extract of Hibiscus sabdariffa calyces extracts (HSE) by close-arterial injection on micturition thresholds (MTs) and on uterine contractions (rate and amplitude). Five doses of HSE were examined (1, 5, 10, 50, and 100 mg/kg) in 3 groups of rats: controls, after bladder inflammation, and after bilateral hypogastric neurectomy. In some rats, uterine contractions were induced by injection of oxytocin (OT) and the effect of HSE was compared with that of nifedipine. HSE increased MTs in a dose-dependent manner in all groups. Neither atropine (0.1 mg/kg) nor propranolol (0.4 mg/kg) had significant effects on cystometric parameters. They also did not affect the responses obtained by HSE on cystometric parameters. As with bladder response, HSE inhibited both the rate and amplitude of uterine contractions in all groups in a dose-dependent manner. The uterine response to HSE was not affected by administration of either atropine or propranolol. A slight, but significant, reduction of contraction amplitude by HSE in the OT precontracted uteri was only noted at a dose of 500 mg/kg. Nifedipine was more potent than HSE in reducing uterine contraction amplitude. The present work documents inhibition by HSE of the rat bladder and uterine contractility in a dose-dependent manner via a mechanism unrelated to local or remote autonomic receptors or calcium channels. However, further investigation is needed to establish the exact mechanism of action.

Objectives: To clarify the anatomy necessary for the nerve sparing Okabayashi's radical hysterectomy, we meticulously separated the blood vessels and connective tissues to preserve the pelvic splanchnic nerve, the hypogastric nerve, and the bladder branch of the inferior hypogastric plexus under magnification (x2.5) during the Okabayashi radical hysterectomy., Methods: Twenty-four patients (FIGO stage IB, n=22, and stage IIA, n=2) underwent meticulous nerve sparing radical hysterectomy during 2004 to 2006. Postoperative assessment of bladder function consisted of the time to (a) achieve a postvoid residual urine volume (PVR) less than 50 ml, (b) obtain a sensation of bladder fullness, and (c) obtain satisfaction of micturition., Results: Isolation of the deep uterine vein could preserve one of the branches of the pelvic splanchnic nerve. The hypogastric nerve in the lateral rectal wall was isolated to the inferior hypogastric plexus. During the division of the posterior leaf of the vesicouterine ligament (VUL), isolation of the inferior vesical vein could reveal the bladder branch from the inferior hypogastric plexus. Only the uterine branch from the inferior hypogastric plexus was isolated and divided. Then, the T-shaped nerve plane consisting of the hypogastric nerve, the pelvic splanchnic nerve and the bladder branch from the inferior hypogastric plexus is preserved. Urinary functions: (a) 11 out of 24 patients had measured PVR of less than 50 ml by postoperative day (POD) 14 and all patients had achieved this by day 21 (mean POD: 14.64+/-2.04). (b) Twenty-two out of 24 patients reported a sensation of bladder fullness by POD 14 and all by POD 21 (mean POD: 11.25+/-1.78). (c) Seventeen out of 24 patients reported satisfaction of micturition by POD 14 and all by POD 21 (mean POD: 12.34+/-2.32)., Conclusion: In order to accomplish the nerve sparing Okabayashi's radical hysterectomy, it is necessary to meticulously divide the posterior leaf of the vesicouterine ligament. By the separation of the inferior vesical vein in the posterior leaf of the vesicouterine ligament, the bladder branch from the inferior hypogastric plexus can be identified and preserved. All patients recovered their urinary function completely by POD 21.

Specialized lymphocytes, called uterine Natural Killer (uNK) cells, appear in human and rodent uteri and become abundant at implantation sites during decidualization and early pregnancy. The hallmark of human uNK cells is intense expression of CD56, a neural cell adhesion glycoprotein (NCAM-1) while mature (granulated) mouse uNK cells express asialoGM1, a brain ganglioside. Murine uNK cells initiate the normal structural changes induced in maternal spiral arteries by pregnancy but regulation of their recruitment, localization and activation is incompletely understood. To address whether uNK cell distribution is co-localized with nerve fiber distribution, sections of gestation day (gd) 6-12 implantation sites from C57BL/6 (B6) mice were studied. Nerve fibers reactive with antibodies to pan neurofilament 150 kD or with tyrosine hydroxylase, an enzyme restricted to sympathetic fibers, were present the walls of branches from the uterine artery in the mesentery. Reactivity was lost as the vessels crossed the myometrium and entered endometrium/decidua. Periodic Acid Schiffs reactive uNK cells were absent from the mesentery and enriched in decidua basalis where they transcribed NCAM-1 and associated with non-innervated segments of the uterine arteries, including spiral arteries. These data suggest that the localization and activation of mature uNK cells are unlikely to be neurotransmitter regulated.

Radical hysterectomy has been performed for invasive cervical cancer, and autonomic nerve-sparing procedures have been developed to preserve bladder function. To perform and improve the nerve-sparing radical hysterectomy, it is important to understand anatomy of the intra pelvic fasciae, specially vesico-uterine ligament (VUL), because most of injuries to the nerves occurred during incision of the VUL in radical hysterectomy procedures. The objectives of the present study were to provide histological understanding of major structures found in nerve-sparing radical hysterectomy. Serial macroscopic slices (15-20 mm thick) from five female pelves were trimmed and prepared for paraffin-embedded histology. We noted an anatomical entity as "the visceroparietal fascial bridge", which corresponds with the macroscopically identified arcus tendineus fasciae pelvis. A histologically identifiable neurovascular pedicle to the bladder neck corresponded with the deep portion of VUL. These findings could help better preservation of autonomic nerves during radical hysterectomy and improve patient's quality of life after the operation. Translation of surgical anatomy into anatomic terminology enables us to have fruitful discussions with persuasive power by excluding any bias from individual surgeons.

This study describes the innervation of uterine fibroids in a retrospective survey of archived material. A total of 24 uteri containing fibroids were identified; four nulliparous uteri with single large fundal fibroids (200 - 320 g) and 20 multiparous uteri with one, or more, fibroids (80 - 230 g). Tissue blocks from the uterine isthmus and the fibroids, were identified, sectioned and stained for nerves with anti-S100 using a standard immunohistochemical regimen. Normal uterine innervation includes concentrations of nerves in the subserosal layer and at the endometrial-myometrial interface with sparse neurovascular bundles distributed throughout the myometrial stroma. Nulliparous uteri with single large fibroids demonstrated relatively normal patterns of innervation with nerves distributed throughout the stroma of the fibroid. In multiparous uteri with fibroids, there were no nerves detectable in the substance of the fibroids. Increased numbers of nerve fibres were observed in the pseudo-capsule of some fibroids and may reflect compression of normal myometrial tissue and their contained nerves, or, a minor degree of nerve fibre proliferation. This study demonstrates that fibroids in multiparous uteri do not contain nerves. Single, large nulliparous fibroids situated at the uterine fundus appear to contain relatively normal patterns of innervation.

Objective: To evaluate the efficacy of laparoscopic uterosacral nerve (LUNA) alone vs. LUNA plus presacral neurectomy (PN) in the treatment of primary dysmenorrhea., Study Design: Seventy-four patients were randomly allocated to LUNA alone or LUNA plus PN. Evaluation of severity of menstrual pain was based on multidimensional scoring., Results: Sixty-seven patients were eligible for analysis (35 LUNA alone, 32 LUNA plus PN). Baseline demographic features were comparable between the 2 groups. There was no difference between them in the proportion of improvement in dysmenorrhea at 3 months of follow-up (69% for LUNA vs. 73% for LUNA plus PN, p = 0.923), and the results were maintained at 6 and 12 months of follow-up. More surgical complications were found in the LUNA plus PN group., Conclusion: For patients with primary dysmenorrhea, LUNA plus PN has no additive therapeutic advantage over LUNA alone, and more surgical complications may be encountered.

Background: Uterine natural killer (uNK) cells are the most abundant leukocytes in pre-implantation endometrium and early pregnancy deciduas in humans and rodents. They are associated with structural changes in maternal spiral arteries but regulation of their recruitment and activation is incompletely understood. The major subpopulation of uNK cells in humans expresses CD56, the neural cell adhesion molecule (NCAM)-1 while their counterpart in mouse expresses asialoGM1, a brain ganglioside. Sympathetic nerves express NCAM-1 which mediates homotypic binding. Sympathetic fibers innervate the mesometrial vasculature but their relationship to the myometrial and decidual uNK cell recruitment is unknown., Objective: The present study aims to explore positional relationship between natural killer cells and distribution of nerves in decidualized mouse uterus., Methods: Immunohistochemistry and mRNA expression for the enzyme tyrosine hydroxylase were used to map sympathetic nerve fibre distribution within C57BL/6 implantation sites and to address a relationship with uNK cells., Results: Tyrosine hydroxylase positive neurons were identified in the mesometrium closely associated with uterine arteries. Staining became gradually vanished as the nerves crossed the myometrium and entered the decidualized uterus. No neuronal stain was associated with the spiral arteries. Periodic Acid Schiff's reactive uNK cells were absent from the mesentery, but abundant in decidua basalis where they are associated with non-innervated vessels., Conclusion: Data suggest that the recruitment of uNK progenitor cells to the uterus is unlikely to be dependent on signaling by the sympathetic nervous system.

This study describes the innervation of the uterus with a histopathological diagnosis of adenomyosis in a retrospective survey of two groups of uteri. Group 1 consisted of 17 histologically-normal, parous uteri and eight nulliparous uteri. Group 2 consisted of 23 parous uteri with the histopathological diagnosis of adenomyosis. Tissue sections from the uterine isthmus were stained for nerves with PGP 9.5 using a standard immunohistochemical regimen. In group 1 (n = 25, normal histological report), normal innervation of the uterine isthmus included concentrations of nerves in the subserosal layers and at the endometrial-myometrial interface with sparse, neurovascular bundles distributed throughout the myometrial stroma. In group 2, (n = 23 with adenomyosis), there were no nerves in areas of adenomyosis and absence of nerves at the endometrial-myometrial nerve plexus. Focal proliferation of small-diameter nerve fibres was observed at the margins of adenomyosis in some uteri. Subserosal nerve fibres were still present in those sections that extended to include this region. Adenomyosis is associated with loss of nerve fibres at the endometrial-myometrial interface and absence of nerve fibres in the adenomyosis.

The purpose of this study was to determine whether primary sensory neurons that innervate the uterus receive convergent input from the colon. To test this, in the rat, cell bodies of colonic and uterine dorsal root ganglia were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and bilaterally into the uterine horns. Ganglia were harvested, cryoprotected and cut into 20 microm slices to identify positively stained cells for fluorescent microscopy. Up to 5% of neurons were colon-specific or uterus-specific, and 10-15% of labeled ganglion neurons innervate both viscera in the L1, L2, L6 and S1-S3 levels. These results suggest a novel form of visceral sensory integration in the dorsal root ganglion that may underlie comorbidity of many functional pain syndromes.

Central nervous system neurons process information converging from the uterus, colon, and bladder, partly via the hypogastric nerve. This processing is influenced by the estrous cycle, suggesting the existence of an estrous-modifiable central nervous system substrate by which input from one pelvic organ can influence functioning of other pelvic organs. Here, we tested predictions from this hypothesis that acute inflammation of colon, uterine horn, or bladder would produce signs of inflammation in the other uninflamed organs (increase vascular permeability) and that cross-organ effects would vary with estrous and be eliminated by hypogastric neurectomy (HYPX). Under urethane anesthesia, the colon, uterine horn, or bladder of rats in proestrus or metestrus, with or without prior HYPX, was treated with mustard oil or saline. Two hours later, Evans Blue dye extravasation was measured to assess vascular permeability. Extravasation was increased in all inflamed organs, regardless of estrous stage. For rats in proestrus, but not metestrus, either colon or uterine horn inflammation significantly increased extravasation in the uninflamed bladder. Much smaller cross-organ effects were seen in colon and uterine horn. HYPX reduced extravasation in the inflamed colon and inflamed uterine horn, but not the inflamed bladder. HYPX eliminated the colon-to-bladder and uterine horn-to-bladder effects. These results demonstrate that inflaming one pelvic organ can produce estrous-modifiable signs of inflammation in other pelvic organs, particularly bladder, and suggest that the cross-organ effects involve the hypogastric nerve and are at least partly centrally mediated. Such effects could contribute to co-occurrence and cyclicity of distressing pelvic disorders in women.

Objective: To assess and compare the laparoscopic uterine nerve ablation (LUNA) and the vaginal uterosacral ligament resection (VUSR) in postmenopausal women with chronic pelvic pain (CPP)., Study Design: Eighty postmenopausal women with intractable and severe midline CPP were randomized to undergo LUNA or VUSR. Costs of two surgical procedures were assesses. Cure rate, severity of CPP, and deep dyspareunia were also evaluated after 6 and 12 months from surgery., Results: The mean cost of LUNA resulted significantly higher in comparison with VURS (2078+/-637 versus 1497+/-297, P<0.001). The cure rate was not significantly different between the two groups at 6 (33/40, 82.5% versus 35/40, 87.5% for groups A and B, respectively; P=0.530; RR 0.94, 95% CI 0.78-1.13), and 12 months (27/36, 75.0% versus 28/38, 73.7%, for groups A and B, respectively; P=0.901; RR 0.90, 95% CI 0.78-1.33) of follow-up. At same times, a significant (P<0.01) decrease in severity of CPP and deep dyspareunia was observed in both groups with no difference between them., Conclusions: Both LUNA and VUSR are equally effective surgical treatments in postmenopausal women with central CPP but VUNR is significantly cheaper than LUNA.

Ion channels are interesting molecules since they mediate not only uterine contraction but also uterine relaxation. We have examined the expression, function, and correlation between the large conductance calcium-activated potassium (BKCa) channel, beta2 adrenoceptor (AR), and long-lasting (L) type calcium (Ca2+) channel. These are the main channels and receptor that are involved in the uterine contraction/ relaxation process. Our evidence has shown that BKCa channel is closely correlated with beta2 AR in mediating uterine relaxation. Both proteins are situated in close proximity on the plasma membrane of human myometrium and are downregulated approximately 50% after the onset of labor. Interestingly, L type Ca2+ channel, which involves in the contraction pathway, seems to be in the same compartmentation as BKCa channel/ beta2 AR macromolecular complex. Further studies are now being conducted to identify the signaling complex components that could potentially be a target for new tocolytic agents.