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The human vaginal epithelium is a crucial component of numerous reproductive processes and serves as a vital protective barrier against pathogenic invasion. Despite its significance, a comprehensive exploration of its molecular profiles, including molecular expression and distribution across its multiple layers, has not been performed. In this study, we perform a spatial transcriptomic analysis within the vaginal wall of human fetuses to fill this knowledge gap. We successfully categorize the vaginal epithelium into four distinct zones based on transcriptomic profiles and anatomical features. This approach reveals unique transcriptomic signatures within these regions, allowing us to identify differentially expressed genes and uncover novel markers for distinct regions of the vaginal epithelium. Additionally, our findings highlight the varied expressions of keratin ( KRT ) genes across different zones of the vaginal epithelium, with a gradual shift in expression patterns observed from the basal layer to the surface/superficial layer. This suggests a potential differentiation trajectory of the human vaginal epithelium, shedding light on the dynamic nature of this tissue. Furthermore, abundant biological processes are found to be enriched in the basal zone by KEGG pathway analysis, indicating an active state of the basal zone cells. Subsequently, the expressions of latent stem cell markers in the basal zone are identified. In summary, our research provides a crucial understanding of human vaginal epithelial cells and the complex mechanisms of the vaginal mucosa, with potential applications in vaginal reconstruction and drug delivery, making this atlas a valuable tool for future research in women's health and reproductive medicine.

Congenital anomalies of the female reproductive tract that present with primary amenorrhea involve Müllerian aplasia, also known as Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), and cervical and vaginal anomalies that completely obstruct the reproductive tract. Karyotype abnormalities do not exclude the diagnosis of MRKHS. Familial cases of Müllerian anomalies and associated malformations of the urinary and skeletal systems strongly suggest a complex genetic etiology, but so far, the molecular mechanism in the vast majority of cases remains unknown. Primary amenorrhea may also be the first presentation of complete androgen insensitivity syndrome, steroid 5α-reductase type 2 deficiency, 17β-hydroxysteroid dehydrogenase type 3 deficiency, and Leydig cells hypoplasia type 1; therefore, these disorders should be considered in the differential diagnosis of the congenital absence of the uterus and vagina. The molecular diagnosis in the majority of these cases can be established.

Introduction: One of the transitional zones of the human body is situated in the cervix uteri. The developmental differentiation of epithelial and stromal characteristics in such a region is of high clinical interest. However, few studies have focused on the development of this region, and information in anatomical and clinical textbooks is limited. We therefore examined the development of the human vaginal fornix and the cervix uteri during prenatal development., Materials and Methods: We examined 29 female embryos and fetuses between 20 and 34 weeks and two newborns using histology and immunohistochemistry., Results: The characteristic shape of the portiocervicis and the vaginal fornix first became visible in mid-term fetuses because of the different muscular coats and of an uncategorized Müllerian-derived epithelium, which was rapidly replaced by a multilayered squamous epithelium. Only thereafter, in older fetuses, were there organogenetic differentiation of the epithelia and the underlying stroma of the cervical canal. UGS-derived p63/CK17-positive cells could be identified as precursor cells for the squamous epithelium, and Müllerian-derived CK7-positive cells for the columnar-type epithelium. Both cell types and different stromal zones were already present in a prenatal transformation zone. Initial functional differentiation could be observed in perinatal stages., Conclusions: Our results on prenatal human development strongly support the view that two different cell lineages meet at the transitional zone of the cervix uteri and that these lineages depend on alternative signals from the underlying stromal compartment., (© 2021 The Authors. Clinical Anatomy published by Wiley Periodicals LLC on behalf of American Association of Clinical Anatomists.)

Oviduct, uterus, and vagina are derived from Müllerian ducts. But only in the vagina, the epithelium differentiates into stratified layers. Organ-specific secreted factors derived from the stroma of a neonatal mouse induce epithelial differentiation in the female reproductive tracts. However, the effects of the components and mechanical property of extracellular matrix (ECM) on the regulation of gene expression in the mesenchymal cells of neonatal stroma and differentiation of epithelium in the female reproductive tracts have been overlooked. In the present study, we have developed a simple 3D neonatal vaginal model using clonal cell lines to study the effect of ECM's components and stiffness on the epithelial stratification. Transcriptome analysis was performed by DNA-microarray to identify the components of ECM involved in the differentiation of vaginal epithelial stratification. The knockdown experiment of the candidate genes relating to vaginal epithelial stratification was focused on fibromodulin (Fmod), a collagen cross-linking protein. FMOD was essential for the expression of Bmp4, which encodes secreted factors to induce the epithelial stratification of vaginal mesenchymal cells. Furthermore, stiffer ECM as a scaffold for epithelial cells is necessary for vaginal epithelial stratification. Therefore, the components and stiffness of ECM are both crucial for the epithelial stratification in the neonatal vagina., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While developments in gynecologic health research continue advancing, relatively few groups specifically focus on vaginal tissue research for areas like wound healing, device development, and/or drug toxicity. Currently, there is no standardized animal or tissue model that mimics the full complexity of the human vagina. Certain practical factors such as appropriate size and anatomy, costs, and tissue environment vary across species and moreover fail to emulate all aspects of the human vagina. Thus, investigators are tasked with compromising specific properties of the vaginal environment as it relates to human physiology to suit their particular scientific question. Our review aims to facilitate the appropriate selection of a model aptly addressing a particular study by discussing pertinent vaginal characteristics of conventional animal and tissue models. In this review, we first cover common laboratory animals studied in vaginal research-mouse, rat, rabbit, minipig, and sheep-as well as human, with respect to the estrus cycle and related hormones, basic reproductive anatomy, the composition of vaginal layers, developmental epithelial origin, and microflora. In light of these relevant comparative metrics, we discuss potential selection criteria for choosing an appropriate animal vaginal model. Finally, we allude to the exciting prospects of increasing biomimicry for in vitro applications to provide a framework for investigators to model, interpret, and predict human vaginal health.

During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.

Introduction: Androgens have been shown to exert beneficial effects on vaginal physiology, at least partially independent of their aromatization to estrogens. Androgen deficiency in the vagina and in the other genitourinary tissues contributes to the development of vulvovaginal atrophy and genitourinary syndrome of menopause, resulting in impaired arousal and lubrication and dyspareunia., Objectives: To summarize the role of testosterone in modulating vaginal structure and function., Methods: A qualitative review of the relevant literature on the topic was performed using the PubMed database. We present a summary of preclinical and clinical evidence supporting the involvement of testosterone (T) in vaginal physiopathology and discuss it in terms of the role of the vagina in female sexual response., Results: Androgens are important in the differentiation of the vagina and in maintaining trophic and functional actions in postnatal life, as suggested by the detection of the androgen receptor and of the key enzymes involved in androgen synthesis. T is essential for the integrity of vaginal tissue structure (including non-vascular smooth muscle thickness and contractility and collagen fiber compactness) and for the complex neurovascular processes that regulate arousal and lubrication (vascular smooth muscle relaxation via the NO/cGMP/PDE5 pathway, nerve fiber density and neurotransmission). T has also been reported to modulate nociception, inflammation, and mucin secretion within the vagina. Available and potential androgen-based treatments for vulvovaginal atrophy/genitourinary syndrome of menopause and for other conditions leading to female genital arousal disorder and dyspareunia are presented., Conclusions: The vagina is both an androgen-target and synthesis organ. Preclinical and clinical data consistently suggest that T plays an important role in maintaining vaginal health and genital sexual function. Maseroli E, Vignozzi L. Testosterone and Vaginal Function. Sex Med 2020;8:379-392., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Cloacal malformations are characterized by the confluence of the lower urinary tract, the female reproductive tract, and the rectum to create a common channel with a single opening on the perineum. The presence of a cloaca is a normal phase of early human embryological development. Between the 4 th and 7 th weeks of gestation, the cloaca undergoes subdivision to form the hindgut and urogenital sinus. Failure of this process results in the congenital anomaly termed persistent cloaca (PC). The term urorectal septum malformation sequence (URSMS) is also used to describe this anomaly. The classic description of this process which is still cited in many standard textbooks dates from the 19 th century. However, this has been increasingly called into question by the findings of studies using modern scientific methodology. Urogenital sinus anomalies are defined by the confluence of the urethra and vagina to form a common channel of varying length with a single perineal opening. In this condition, the anorectal canal opens separately on the perineum. The presence of a urogenital sinus represents a transient phase of the normal development of the lower genital tract in the female fetus. However, the form of urogenital sinus most commonly encountered in the developed world is a feature of disordered sexual differentiation and does not arise simply from the persistence of the anatomical structure which is a feature of normal fetal development., Competing Interests: None

Objective: Introduction: The rapid development of perinatal gynecology requires from the anatomists comprehensive studies of the patterns of prenatal morphogenesis and the development of topographic and anatomical relationships of female reproductive organs in the human fetuses of different age groups. The aim: To study the development and formation of the vaginal topography in the prenatal period of human ontogenesis., Patients and Methods: Materials and methods: The study has been conducted based on 23 series of histological and topographic-anatomical sections of human prefetuses aged 9-12 weeks with 31.0-80.0 mm of crown-rump length (CRL) and 83 specimens of female human fetuses aged 4-9 months with 81.0-345.0 mm of CRL by means of a complex of adequate morphological methods of investigation., Results: Results and conclusions: Vaginal formation occurs during the 9th week of embryogenesis (prefetuses of 31.0-41.0 mm of CRL) due to the fusion of two different embryonic structures: mesodermal paramesonephral ducts and endodermal urogenital sinus. In this case, the caudal regions of the paramesonephral ducts are transformed into the uterus and the superior two thirds of the vagina, and the inferior third of the vagina develops from the urogenital sinus. Common uterovaginal canal, divided into right and left cavities by mesenchymal septum, is formed in the female prefetuses of 38.0-43.0 mm of CRL due to the fusion of the caudal regions of the paramesonephral ducts in the area of the posterior wall of the urogenital sinus. Complete dissolving of the septum of the uterovaginal canal occurs in prefetuses of 55.0-58.0 mm of CRL. The anterior and posterior vaginal vaults of the same depth are formed in 5-month-old fetuses. Canalization of vagina in the caudo-cranial direction is observed in the fetuses of 170.0-185.0 mm of CRL, with no clear boundary between the uterovaginal canal and the urogenital sinus. The vaginal epithelium in the upper third part originates from the uterovaginal canal, and in the lower two thirds of the vagina - from the urogenital sinus. In the 6-month-old fetuses there was detected the variability of the shape of the superior, middle and inferior third of the vagina, namely: oval (5 cases), elongated-oval (2 cases), stellate (1 case); in the lower third, the H-shaped form was predominantly found (6 fetuses). The proliferation of the hymen membrane occurs in fetuses of 220.0-245.0 mm of CRL. The absence of timely proliferation of the hymen membrane can lead to its atresia, and its premature proliferation causes the appearance of transverse vaginal septa.

The vaginal vestibule has not been the subject of a dedicated journal article. Recent terminology has suggested its division into anterior and posterior components. The case for this division has not yet been assessed. Both components extend laterally from the hymen to the junction with the labia minora. The posterior vaginal vestibule is proposed to extend from the posterior aspect of the hymen to the anterior edge of the perineum whilst the anterior vestibule extends from the posterior aspect of the hymen to just below the clitoris. Anatomical considerations (differing layers) might firstly support the above division. The posterior vestibule, by necessity, is far more flexible with the superficial aspect (approximately 1.5 cm), anatomically and histologically, comprising skin and subcutaneous tissue, with perineal musculature deep to this. In turn, it is more likely to be subject to obstetric and surgical considerations than the anterior vaginal vestibule. Obstetric trauma, in particular, would tend to create defects, particularly at its posterior margin. Many dermatological and microbiological considerations may be common to both anterior and posterior vestibule. Any dermatological condition of the vestibule can result in sexual dysfunction and can be complicated by secondary muscular spasm. Congenital anomalies will differ anteriorly and posteriorly. Multiple considerations can be identified to support the case for division of the vaginal vestibule into anterior and posterior components. Neurourol. Urodynam. 36:979-983, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The Müllerian duct develops into the oviduct, uterus, and vagina, all of which are quite distinct in their morphology and function. The epithelial fate of these female reproductive organs in developing mice is determined by factors secreted from the stroma; however, how stromal differentiation occurs in the female reproductive organs derived from the Müllerian duct is still unclear. In the present study, roles of retinoic acid (RA) signaling in developing female reproductive tracts were investigated. Retinol dehydrogenase 10 (RDH10) and aldehyde dehydrogenase family 1 subfamily A2 (ALDH1A2) mRNAs and proteins and transactivation activity of endogenous RA were found in the stroma of proximal Müllerian ducts and gradually decreased from the proximal to caudal regions in fetal mice. In organ-cultured Müllerian ducts, retinaldehyde or RA treatment induced uterine epithelial differentiation, defined as a layer of columnar epithelial cells negative for oviductal and vaginal epithelial markers. In contrast, inhibition of RA receptor (RAR) signaling induced vaginal epithelial differentiation, characterized as vaginal epithelial marker genes-positive stratified epithelium. Grafting experiments of the organ-cultured Müllerian duct revealed irreversible epithelial fate determination. Although RAR did not directly bind to the homeobox A10 (Hoxa10) promoter region, RA-RAR signaling stimulated Hoxa10 expression. Thus, RA-RAR signaling in the Müllerian duct determines the fate of stroma to form the future uterus and vagina., Competing Interests: The authors declare no conflict of interest.

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development., Competing Interests: The authors declare no conflict of interest.

Background: The explanation of uterine and vaginal embryogenesis in humans still poses many controversies, because it is difficult to assess early stages of an embryo. The literature review revealed many disagreements in Mullerian theory, inciting some authors to propose new embryological hypotheses. In the original Mullerian theory: the paramesonephral ducts form the Fallopian tubes, uterus and vagina; the mesonephral ducts regress in female embryos., Aims: The aim of this article is to investigate the development of Mullerian ducts in humans, using comparative analysis of fundamental embryological theory and various utero-vaginal anomalies., Material and Methods: Between 1998 and 2015, 434 patients with various uterovaginal malformations had been operated on at the Scientific Centre of Obstetrics Gynaecology and Perynatology in Moscow. The anatomies of the uterovaginal malformations in these patients were diagnosed with ultrasound and MRI and then verified during surgical correction by laparoscopy., Results: A systematic comparison of uterovaginal malformations to those in the literature has allowed us to formulate a new theory of embryonic morphogenesis. The new theory is significantly different: ovary, ovarian ligamentum proprium, and ligamentum teres uteri derive from gonadal ridges; Fallopian tubes and vagina completely develop from mesonephral ducts. The uterus develops in the area of intersection between the mesonephral ducts with gonadal ridges by the fusion of the two., Conclusions: The new theory may to induce future embryological studies. The hypothetic possibility that the ovary and endometrium derive from the gonadal ridges could be the key to understanding the enigmatic aetiologies of extragenital and ovarian endometriosis.

Objective: Studies on the development of the embryological and fetal development of the cervix and the vagina are rare and mostly go back to the first decades of the last century. The aims of this review were to present the latest knowledge concerning the developmental origin of cervical and vaginal epithelium and to point out new results in the context of different clinical findings., Materials and Methods: Relevant studies published between 1910 and 2013 were identified via PubMed, MEDLINE, OVID, Web of Science, and EMBASE. The reference lists of retrieved articles were reviewed to locate additional articles. Each abstract was reviewed, and the appropriate publications were obtained and reviewed as well. A total of 33 articles and 8 book chapters were selected for citation in this review., Results: New objective findings clearly show that human prenatal epithelialization of the cervix and vagina results in 3 morphogenetically determined units: (i) the Müllerian columnar epithelium of the endocervix, (ii) the Müllerian squamous epithelium of the ectocervix and the upper vagina, and (iii) the vaginal squamous epithelium of the lower vagina., Conclusions: These results are of high clinical relevance and may provide new insight into the histogenesis of ectopy, vaginal adenosis, and the congenital transformation zone. They should be added to the explanations in gynecological, colposcopical, and gynecopathological textbooks.

Introduction: The aim of this study was to evaluate the characteristics of inguinal hernia (IH) and patent processus vaginalis (PPV) in term and preterm infants less than the age of 6months., Method: Between January 2004 and December 2012, 246 term and 165 preterm infants underwent laparoscopic herniorrhaphy within the first 6months of life. Preoperative clinical presentation and intraoperative anatomical findings during the laparoscopic procedure were evaluated. Additionally, initial side of hernia, laterality of IH and PPV were analyzed in term and preterm infants., Results: In the group of term infants, most infants presented with a primary right-sided IH (58.5%) versus 17.9% left-sided and 23.6% bilateral IH. Babies with primary unilateral IH were found to have a contralateral PPV in 41.0% of cases. A difference between left-sided PPV and right-sided PPV could not be identified. In the group of preterm infants, initial bilateral presentation was predominant (38.8%) versus right-sided (30.3%) and left-sided IH (30.9%). Infants with primary unilateral IH were found to have a contralateral PPV in 56.4%. We identified a slight difference between left-sided PPV (54.0%) and right-sided PPV (58.8%)., Conclusion: IH is predominantly right sided in term infants, whereas preterm infants mostly present with bilateral IH. The incidence of PPV was found to be significantly higher in the preterm group. Regarding the incidence of a contralateral PPV in term and preterm infants, no difference between initial left-sided and right-sided IH could be identified between both groups., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Herlyn-Werner-Wunderlich syndrome is a congenital urogenital malformation that is associated with a uterus didelphys and a longitudinal vaginal septum, resulting in a blind hemivagina and ipsilateral renal agenesis. Clinical presentation is highly variable, delaying diagnosis and leading to important complications., Clinical Case: We present the case of a 13-year-old female who was diagnosed with Herlyn-Werner-Wunderlich syndrome following an acute abdomen due to a right tubo-ovarian abscess. She had a vaginal septum giving rise to a right blind hemivagina. It was microperforated, causing intermittent genital bleeding. This hematocolpos was colonized by microorganisms that ascended to the pelvic cavity, causing right tuboovarian abscess. Nuclear magnetic resonance imaging provided theWernermost diagnostic information. We performed a vaginal septum resection, and both hemiuteros communicated with a single vagina, resulting in an asymptomatic patient., Conclusion: Herlyn-Werner-Wunderlich syndrome is a little known entity and can be presented atypically, resulting in diagnostic difficulty and treatment delay. It is important to be aware of this syndrome in order to avoid irreversible complications.

Müllerian duct anomalies are a group of uncommon and underdiagnosed entities, which cause specific symptoms in adolescent females and may be associated with infertility as well as adverse pregnancy outcomes. These malformations occur as a result of an arrest or abnormal development of the Müllerian ducts in different stages of the female reproductive tract during gestation. Obstructed hemivagina and ipsilateral renal anomaly syndrome (OHVIRA), formerly known as the Herlyn-Werner-Wunderlich syndrome, is a rare entity characterized by the presence of a uterus didelphys with an obstructed hemivagina cause by a vaginal septum and the association of a renal anomaly (most commonly renal agenesis) ipsilateral to the obstruction. This syndrome may remain undiagnosed during childhood and usually becomes symptomatic after menarche, causing obstructive symptoms. Occasionally it may be identified after the evaluation of a patient with infertility or recurrent pregnancy loss. The clinical diagnosis is very challenging and requires imaging studies in which ultrasound and MRI play an essential role in the diagnosis, classification and treatment plan. Opportune diagnosis and treatment achieve complete improvement of symptoms, adequate reproductive prognosis and avoid major complications such as endometriosis, pelvic adhesions and infertility. The purpose of this review is to demonstrate the pathophysiology, clinical manifestations, diagnostic methods and treatment of the obstructed hemivagina and ipsilateral renal anomaly syndrome.

Objectives: To retrospectively review cases of unilateral vaginal or cervical atresia with ipsilateral renal agenesis at our institution and to analyze the clinical presentation, diagnostic pitfalls, management, and embryological implications for the vaginal origin that arise from this syndrome., Study Design: A retrospective observational study that included 52 patients diagnosed with this syndrome between 1998 and 2008 at Peking Union Medical College Hospital., Results: The median age at diagnosis was 21.5 years, and the median time between the first onset of symptoms and diagnosis was 12 months. The most common presenting complaints were dysmenorrhea, purulent discharge and irregular spotting, despite the wide spectrum of symptoms at referral. Patients with and without a communication between the two hemivaginas or hemiuteri had different clinical characteristics. Of the patients, 59.6% had an obstruction on the right side. Of patients who had received a check-up prior to referral, 92.9% (n=28) had been misdiagnosed, and 53.9% had received inappropriate surgery as therapy. The pathology of the resected septum showed squamous epithelium in 13 samples, while 5 samples had epithelium with paramesonephric characteristics., Conclusion: Knowledge of the origins and clinical presentation of this syndrome is the foundation for correct and timely diagnosis and treatment. Moreover, this unique anomaly may offer essential clues for determining the embryological origins of the vagina and cervix., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5' sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: It is still unclear whether the longitudinal anal muscles or conjoint longitudinal coats (CLCs) are attached to the vagina, although such an attachment, if present, would appear to make an important contribution to the integrated supportive system of the female pelvic floor., Materials and Methods: Using immunohistochemistry for smooth muscle actin, we examined semiserial frontal sections of 1) eleven female late-stage fetuses at 28-37 weeks of gestation, 2) two female middle-stage fetus (2 specimens at 13 weeks), and, 3) six male fetuses at 12 and 37 weeks as a comparison of the morphology., Results: In late-stage female fetuses, the CLCs consistently (11/11) extended into the subcutaneous tissue along the vaginal vestibule on the anterior side of the external anal sphincter. Lateral to the CLCs, the external anal sphincter also extended anteriorly toward the vaginal side walls. The anterior part of the CLCs originated from the perimysium of the levator ani muscle without any contribution of the rectal longitudinal muscle layer. However, in 2 female middle-stage fetuses, smooth muscles along the vestibulum extended superiorly toward the levetor ani sling. In male fetuses, the CLCs were separated from another subcutaneous smooth muscle along the scrotal raphe (posterior parts of the dartos layer) by fatty tissue., Conclusion: In terms of topographical anatomy, the female anterior CLCs are likely to correspond to the lateral extension of the perineal body (a bulky subcutaneous smooth muscle mass present in adult women), supporting the vaginal vestibule by transmission of force from the levator ani.

Literature on the development of the human vagina is abundant; however, contributions concerning the prenatal development of the entire utero-vaginal anlagen (UVA) are rare or carried out in rodents. The primary epithelial characteristics in the adult vagina and uterus are determined during prenatal development and depend on epithelio-mesenchymal stroma interaction; thus an investigation summarizing the spatiotemporal distribution of relevant molecular markers in the entire human UVA will be of current interest. We phenotyped epithelial and mesenchymal characteristics in sagittal sections from 24 female fetuses of 14-34 weeks of gestation and two female newborns by immunostaining with cytokeratins 8, 13, 14 and 17, p63, bcl-2, bmp4, HOX A13, CD31, VEGF, SMA, Pax2 and vimentin. Epithelial differentiation followed a caudal-to-cranial direction in the UVA. Due to the cytokeratin profile of cytokeratins 8, 13 and 14, the characteristics of the different epithelial zones in the UVA could already be recognized in middle-age fetuses. Vaginal epithelium originated from the urogenital sinus in the lower portion and initiated the transformation of vimentin-positive Müllerian epithelium in the upper vaginal portion. During prenatal development the original squamo-columnar junction was clearly detectable from week 24 onwards and was always found in the cervical canal. Early blc-2 positivity within the surrounding mesenchyme of the entire vagina including the portio region pointed to an organ-specific mesenchymal influence. Prenatal findings in human specimens clearly show that fornix epithelium up to the squamo-columnar junction is of vaginal Müllerian origin, and the cervical epithelium cranial to the squamo-columnar junction is of uterine Müllerian origin and includes cells with enough plasticity to transform into squamous epithelium., (© 2013 The Authors Journal of Anatomy © 2013 Anatomical Society.)

Overactive bladder (OAB) syndrome has a significant deleterious impact on quality of life. After conservative therapy and bladder retaining, antimuscarinic drugs remain the mainstay of OAB management. Oral therapy is associated with frequent side effects, leading to the development of alternative agents and formulations or the use of novel routes of drug administration, such as the vaginal route. The vagina is often ideal for drug delivery because it allows the use of lower doses, maintains steady drug administration levels, and requires less frequent administration than the oral route. With vaginal drug administration, absorption is unaffected by gastrointestinal disturbances, there is no first-pass effect, and use is discreet. The aim of this review is to provide a background overview of vaginal development, anatomy, and physiology and the effect this has on the use of this route for both local and systemic drug delivery, with special reference to OAB management. Vaginal therapy continues to be an underused route of drug delivery. Vaginal administration allows nondaily, low, continuous dosing, which results in stable drug levels and may, in turn, achieve a lower incidence of side effects and improve patient compliance. These benefits must be balanced against inherent patient or physician bias against using this route and the need to overcome cultural, personal, and hygiene-related barriers to this form of therapy. More sophisticated and programmable vaginal rings are being developed for systemic delivery of therapeutically important macromolecules, such as antimuscarinic therapy in OAB management.

Aim: Minimal data are available on the role of pelvic exenteration in patients with recurrent squamous cell carcinoma (SCC) of the pelvic organs. This study aimed to highlight our experience of pelvic exenteration in patients with recurrent and re-recurrent SCC of the pelvic organs., Method: A retrospective review of all patients who underwent pelvic exenteration for recurrent SCC of the pelvic organs arising from the embryological cloaca from 1994 to 2010 was performed., Results: Twenty-four patients (median age 59, range, 27-79 years) underwent pelvic exenteration for recurrent SCC of the anus (18), cervix and upper vagina (2), lower vagina (1) and the vulva (3). Nine patients with anal SCC had undergone abdominoperineal excision prior to pelvic exenteration. Ten (41.7%) patients underwent a complete pelvic exenteration procedure, while sacrectomy was performed in 13 (54.2%) patients. There was no 30-day inpatient mortality. An R0 resection was achieved in 15 (62.5%) patients. Three (12.5%) had R1 resections while 6 (25%) had R2 resections. In the 15 patients with an R0 resection, 7 (46.7%) developed metastatic disease at a median of 18 (range 10-131) months. After a median follow-up of 26 (range 4-169) months, 1- and 2-year overall survival rates were 64% [95% confidence interval (CI), 44-84%] and 57% (95% CI 35-79%), respectively., Conclusion: Pelvic exenteration for recurrent SCC of the cloaca is safe and feasible even after previous salvage surgery. An R0 resection can be achieved in 62.5% of the patients with reasonable early survival though less than published recurrent rectal cancer studies., (Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.)

The Mayer-Rokitansky-Kuster-Hauser is a rare congenital anomaly characterized by lack of vaginal and uterine development variable and normal ovaries. It results from agenesis or hypoplasia Müller duct system. Cervicovaginal agenesis as part of the complex syndrome, is even rarer. We report two cases: adolescent patient with primary amenorrhea, cervicovaginal agenesis and chronic pelvic pain, and a 28-year-old patient with primary amenorrhea, congenital absence of uterus and vagina.

Unresolved questions remain concerning the derivation of the vagina with respect to the relative contributions from the Müllerian ducts, the urogenital sinus, and the Wolffian ducts. Recent molecular and cellular studies in rodents have opened up a large gap between the level of understanding of vaginal development in mice and understanding of human vaginal development, which is based on histology. To compare the findings in mice with human vaginal development and to address this gap, we analysed molecular characteristics of the urogenital sinus, Wolffian ducts, and Müllerian ducts in 8-14-week-old human specimens using immunohistochemical methods. The monoclonal antibodies used were directed against cytokeratin (CK) 14, CK19, vimentin, laminin, p63, E-cadherin, caspase-3, Ki67, HOX A13, and BMP-4. The immunohistochemical analysis revealed that, during weeks 8-9, the epithelium of the Müllerian ducts became positive for p63 as p63-positive cells that originated from the sinus epithelium reached the caudal tip of the fused Müllerian ducts via the Wolffian ducts. The lumen of the fused Müllerian ducts was closed by an epithelial plug that contained both vimentin-positive and vimentin-negative cells. Subsequently, the resulting epithelial tube enlarged by proliferation of basal p63-positive cells. The first signs of squamous differentiation were detected during week 14, with the appearance of CK14-positive cells. According to our results, all three components, namely, the urogenital sinus, Wolffian ducts, and Müllerian ducts, interacted during the formation of the human vagina. The sinus epithelium provided p63-positive cells, the Wollfian ducts acted as a 'transporter', and the Müllerian ducts contributed the guiding structure for the vaginal anlagen. Epithelial differentiation began at the end of the period studied and extended in a caudo-cranial direction. The present study is one of the first to provide up-to-date molecular correlates for human vaginal development that can be compared with the results of cell biological studies in rodents., (© 2012 The Authors. Journal of Anatomy © 2012 Anatomical Society.)

Unlabelled: The (As) arsenic exposure is a risk factor for causing disturbances in the endocrine organs., Objective: To evaluate if sub-chronic As exposure during the pre- and postnatal development causes disturbances in the puberty. Moreover, determine adverse effects of As on the ovarian follicle and adrenocortical cell maturation., Methods: Females adult Wistar rats were exposed to sodium arsenite at 3 ppm calculated as As in drinking water from mating, gestation. Following the birth, the female offspring continued exposured to As via lactation. Weaned pups received the same As treatment as mothers, until they were 1-4 months (mo) old. At these ages, blood sampling and tissue harvest were done. The tissues were fixed in situ with 4% paraformaldehyde in phosphate buffer. After the perfusion the ovaries, uterus, adrenal glands were harvested, dissected out, weighted. The ovaries and the adrenal glands were processed to paraffin and sectioned at 5 μM and stained with hematoxylin and eosin for light microscopy., Statistical Analysis: Comparisons between groups were made by unpaired t-test or nonparametric Mann-Whitney test as appropriate., Results: 100% As treated rats at 1 mo of age were at diestrous stage, with low estradiol E2. As treatment caused disturbances in the morphology of the ovarian cell consisting in DNA damage evidenced by picknotic chromatin, cariorexis, significant cytoplasmic vacuolization and also vasculature damaged. Arrest in follicle maturation was also present., Conclusions: We found that the onset of puberty in the As treated rats was 1 mo delayed since vagina was still closed, the vaginal smear showed that they were at diestrus stage with plasma low E2 levels., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Hydrometrocolpos, occurring in approximately 1/6000 newborn girls, can be caused by a stenotic urogenital sinus, a severe cloacal malformation, but also by other conditions such as an imperforate hymen, a midline vaginal septum and vaginal atresia. The prenatal differential diagnosis of this wide spectrum of conditions is not easy and requires a multidisciplinary approach with follow-up scans and MRI to access the severity of the condition. A non-consanguineous couple was referred in the first pregnancy at 30 weeks. The father, 30 years of age, of Kaukasian origin, and the mother of Asian origin, 26 years of age. Ultrasound at 30 weeks revealed ambiguous genitalia (with suspicion of clitoral hypertrophy), a septated structure located behind the bladder compatible with hydrometrocolpos with a uterine malformation (uterus didelphys), a single umbilical artery, mild ascites and growth on the tenth centile. The differential diagnosis included a vaginal atresia, a urogenital sinus and a more severe cloacal malformation. After serial scans, MRI and counselling by an experienced surgeon the preferential diagnosis of a cloacal malformation was made and a late pregnancy termination was performed. Pathological examination revealed: low vaginal atresia with uterus didelphys, anal atresia with rectovaginal fistula and a normal urinary tractus. The differential diagnosis between hydrometrocolpos due to vaginal atresia or due to a more severe cloacal malformation is not straightforward. Care should be taken in decision making and counselling patients with these complex prenatal malformations.

Background: Which parts of the male urethra correspond to the female urethra? To resolve this question, we need to understand fetal topographical changes in the urethra, its external sphincter and vagina. The vagina joins the mid-course of the primitive urethra and, later "descends" to the vaginal vestibulum., Methods: We examined histological sections of 14 female and 4 male mid-term fetuses., Results: The inferior end of the vagina was consistently embedded in the posterior wall of the urethra at 9-12 weeks. The supero-inferior level of the vaginal merging was lower in larger fetuses. Thus, the sequential variation in levels appeared to reflect the process of vaginal descent. However, in spite of penetration of the vaginal end into the posterior urethral wall, we found no sign of destruction of the urethral wall after vaginal descent in the low-merging types. Before vaginal descent, the female external sphincter extended posterolaterally around the urethra., Conclusion: The vaginal descent is classically regarded as a relative topographical change, but it is likely to be a result of elongation of the proximal urethra in the superior side of the vaginal merging. Conversely, the distal urethra is likely to be incorporated into the vaginal vestibulum by 15 weeks. During these processes, most of the female external sphincter seems to be expelled from the original anterior position into the vestibular wall as the urethrovaginal sphincter. The adult female urethra seems to correspond to the male prostatic urethra superior to the prostatic colliculus., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

In mammals, the female reproductive tract (FRT) develops from a pair of paramesonephric or Müllerian ducts (MDs), which arise from coelomic epithelial cells of mesodermal origin. During development, the MDs undergo a dynamic morphogenetic transformation from simple tubes consisting of homogeneous epithelium and surrounding mesenchyme into several distinct organs namely the oviduct, uterus, cervix and vagina. Following the formation of anatomically distinctive organs, the uniform MD epithelium (MDE) differentiates into diverse epithelial cell types with unique morphology and functions in each organ. Classic tissue recombination studies, in which the epithelium and mesenchyme isolated from the newborn mouse FRT were recombined, have established that the organ specific epithelial cell fate of MDE is dictated by the underlying mesenchyme. The tissue recombination studies have also demonstrated that there is a narrow developmental window for the epithelial cell fate determination in MD-derived organs. Accordingly, the developmental plasticity of epithelial cells is mostly lost in mature FRT. If the signaling that controls epithelial differentiation is disrupted at the critical developmental stage, the cell fate of MD-derived epithelial tissues will be permanently altered and can result in epithelial lesions in adult life. A disruption of signaling that maintains epithelial cell fate can also cause epithelial lesions in the FRT. In this review, the pathogenesis of cervical/vaginal adenoses and uterine squamous metaplasia is discussed as examples of such incidences., (Copyright © 2011. Published by Elsevier B.V.)

Objective: We have suggested to base cancer surgery on ontogenetic anatomy and the compartment theory of tumor permeation in order to improve local tumor control and to lower treatment-related morbidity. Following the validation of this concept for the uterine cervix, proximal vagina and vulva, this study explores its applicability for the distal vagina., Methods: Serial transverse sections of female embryos and fetuses aged 8-17 weeks were assessed for the morphological changes in the region defined by the deep urogenital sinus-vaginal plate complex. Histopathological pattern analysis of local tumor spread was performed with carcinomas of the lower genital tract involving the distal vagina to test the compartment theory., Results: Ontogenetically, the female urethra, urethrovaginal septum, distal vagina and rectovaginal septum represent a morphogenetic unit derived from the deep urogenital sinus-vaginal plate complex. Herein, the posterior urethra, the urethrovaginal septum and the distal vagina form a distinct subcompartment differentiated from the dorsal wall of the urogenital sinus. From 150 consecutive patients with distal vaginectomy as part of their surgical treatment 26 carcinomas of the lower genital tract had infiltrated the distal vagina. All 22 tumors involving the ventral wall invaded the urethra/periurethral tissue. Of the five carcinomas involving the dorsal wall none invaded the rectum/mesorectum., Conclusion: The pattern of local tumor permeation of lower genital tract cancer in the distal vagina can be consistently explained with ontogenetic anatomy and the compartment theory., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is present in at least 1 out of 4,500 female live births and is the second most common cause for primary amenorrhea. It is characterized by vaginal and uterine aplasia in an XX individual with normal secondary characteristics. It has long been considered a sporadic anomaly, but familial clustering occurs. Several candidate genes have been studied although no single factor has yet been identified. Cases of discordant monozygotic twins suggest that the involvement of epigenetic factors is more likely., Methods: Differences in gene expression and methylation patterns of uterine tissue between eight MRKH patients and eight controls were identified using whole-genome microarray analyses. Results obtained by expression and methylation arrays were confirmed by qRT-PCR and pyrosequencing., Results: We delineated 293 differentially expressed and 194 differentially methylated genes of which nine overlap in both groups. These nine genes are mainly embryologically relevant for the development of the female genital tract., Conclusion: Our study used, for the first time, a combined whole-genome expression and methylation approach to reveal the etiology of the MRKH syndrome. The findings suggest that either deficient estrogen receptors or the ectopic expression of certain HOXA genes might lead to abnormal development of the female reproductive tract. In utero exposure to endocrine disruptors or abnormally high maternal hormone levels might cause ectopic expression or anterior transformation of HOXA genes. It is, however, also possible that different factors influence the anti-Mullerian hormone promoter activity during embryological development causing regression of the Müllerian ducts. Thus, our data stimulate new research directions to decipher the pathogenic basis of MRKH syndrome.

Mayer-Rokitansky-Kuster-Hauser (MRKH) is a characteristic syndrome in which the mullerian structures are absent or rudimentary. It is also associated with anomalies of the genitourinary and skeletal systems. There are very few cases reported regarding its association with anorectal malformations, particularly perineal fistulas. To the best of our knowledge, there have not been any reported cases of anal canal stenosis in patients with MRKH. We describe a very rare association of MRKH with anal canal stenosis and multiple renal calculi. The patient underwent corrective surgery for the anomalies and removal of renal calculi. She has been under regular follow-up for the last few months and is doing well., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The microvascularisation of the vaginal wall is studied in foetuses, neonates and infants by injection of agarized Indian ink into the circulation. The purpose of the study is to specify the angioarchitecture of each tunic and their specific drainage. The disposition of microvascularisation of the vaginal wall is superimposed on the orientation of the fibres of the muscular tunic. The orientation of veins of the submucous is plexiform and not longitudinal., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

The developmental origin of vaginal epithelium has been controversial for nearly a century, with speculation that vaginal epithelium originates from the Müllerian duct, Wolffian duct, and/or urogenital sinus. None of these possibilities have been definitively proven or disproven by direct scientific data. To define precisely the origin of vaginal epithelium, epithelial cells of the Müllerian duct, Wolffian duct, or urogenital sinus were fluorescently labeled in mouse embryos by crossing tdTomato-EGFP dual-reporter transgenic mice with transgenic mouse lines that express Cre-recombinase in each type of epithelium. In embryos and newborn mice, the vagina consisted of fused Müllerian ducts plus the sinus vagina of urogenital sinus origin. However, the proportion of the sinus vagina was significantly reduced as the Müllerian vagina grew caudally. By postpartum day 7, the Müllerian vagina extended to the caudal end of the body, whereas the sinus vagina remained only at the junction between the vagina and perineal skin. As the vagina opened in puberty, urogenital sinus epithelium was detected only in the vulva, but not in the vagina. Additionally, from embryo to adult stages, residual Wolffian duct epithelium was present in the dorsolateral stromal wall of the vagina, but not within vaginal or vulvar epithelium. In conclusion, adult mouse vaginal epithelium is derived solely from Müllerian duct epithelium., (Copyright © 2010 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Background: Local tumor spread of cervical cancer is currently considered as radial progressive intra- and extracervical permeation. For radical tumor resection or radiation the inclusion of a wide envelope of tumor-free tissue is demanded. However, this concept may lead to considerable treatment-related morbidity and does not prevent local relapse. We propose an alternative model of local tumor propagation involving permissive compartments related to embryonic development., Methods: We analyzed local tumor spread macroscopically and microscopically in consecutive patients with advanced cervical cancer and post-irradiation recurrences., Results: Macroscopically, all 33 stage I B (>2cm) tumors, 40 of 42 stage II tumors and 32 of 44 stage III B tumors were confined to the embryologically defined uterovaginal (Müllerian) compartment. Local tumor permeation deformed the uterovaginal compartment mirroring the mesenchyme distribution of the Müllerian anlage at the corresponding pelvic level in cases of symmetrical tumor growth. Tumor transgression into adjacent compartments mainly involved the embryologically related lower urinary tract. Compartmental transgression was associated with larger tumor size, paradox improvement in oxygenation and an increase in microvessel density. Post-irradiation pelvic relapse landscapes were congruent with the inflated Müllerian compartment. Microscopically, all locally advanced primary cancers and post-irradiation recurrences were confined to the uterovaginal and lower urinary tract compartments., Conclusion: Cervical cancer spreads locally within the uterovaginal compartment derived from the Müllerian anlage. Compartment transgression is a relatively late event in the natural disease course associated with distinct phenotypic changes of the tumor. Compartmental tumor permeation suggests a new definition of local treatment radicality., (Copyright 2010 Elsevier Inc. All rights reserved.)

Congenital anomalies of the vagina may be isolated to the vagina or be part of a more complex Mullerian tract anomaly with possible fertility concerns. Patient age, complete assessment of the anomaly before surgery, and the psychologic implications for the patient are important components of the initial evaluation and treatment planning. Imaging, including magnetic resonance imaging, should be used to assess the extent of the anomaly and possibly other organ systems involved. Surgeries for imperforate hymen, longitudinal septum, and low thin transverse septum are relatively straightforward. More complicated surgeries should be performed by a specialized surgical team.

Bcl2-modifying factor (Bmf) is a member of the BH3-only group of proapoptotic proteins. To test the role of Bmf in vivo, we constructed mice with a series of mutated Bmf alleles that disrupt Bmf expression, prevent Bmf phosphorylation by the c-Jun NH(2)-terminal kinase (JNK) on Ser(74), or mimic Bmf phosphorylation on Ser(74). We report that the loss of Bmf causes defects in uterovaginal development, including an imperforate vagina and hydrometrocolpos. We also show that the phosphorylation of Bmf on Ser(74) can contribute to a moderate increase in levels of Bmf activity. Studies of compound mutants with the related gene Bim demonstrated that Bim and Bmf exhibit partially redundant functions in vivo. Thus, developmental ablation of interdigital webbing on mouse paws and normal lymphocyte homeostasis require the cooperative activity of Bim and Bmf.

We report a successful case of persistent urogenital sinus associated with a duplicated nonsyndromic form of hydrometrocolpos and ascites diagnosed prenatally. Though urogenital malformations are extremely rare and variable in presentation, the conjugation of those anomalies in a newborn is reported here for the first time. Prenatal ultrasound diagnosis was suspected at 25 weeks' gestation and MRI imaging supported the diagnosis. Periodic ultrasound surveillance was conducted until birth at 35 weeks' gestation by cesarean section. The presumptive diagnosis was confirmed after birth. One month later, the newborn underwent reconstructive surgical intervention with good outcome., (Copyright © 2010 S. Karger AG, Basel.)

The purpose of this study was to review the embryology, classification, imaging features and treatment options of Müllerian duct anomalies. The three embryological phases will be described and the appearance of the seven classes of Müllerian duct anomalies will be illustrated using hysterosalpingography, ultrasound and MRI. This exhibit will also review the treatment options, including interventional therapy. The role of imaging is to help detect, classify and guide surgical management. At this time, MRI is the modality of choice because of its high accuracy in detecting and accurately characterising Müllerian duct anomalies. In conclusion, radiologists should be familiar with the imaging features of the seven classes of Müllerian duct anomalies, as the appropriate course of treatment relies upon the correct diagnosis and categorisation of each anomaly.

Background: Radical hysterectomy based on empirical surgical anatomy to achieve a wide tumour resection is currently applied to treat early cervical cancer. Total mesometrial resection (TMMR) removes the embryologically defined uterovaginal (Müllerian) compartment except its distal part. Non-Müllerian paracervical and paravaginal tissues may remain in situ despite their possible close proximity to the tumour. We propose that in patients with early cervical cancer, the resection of the Müllerian compartment will lead to maximum local tumour control with low morbidity. We also propose that the relatively high rate of pelvic failure after conventional radical hysterectomy, despite adjuvant radiation, might be a consequence of the incomplete removal of the Müllerian compartment. The aim of our study was to test these hypotheses., Methods: We did a prospective trial to assess the effectiveness of TMMR without adjuvant radiation in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB, IIA, and selected IIB cervical cancer. We also generated MRI-based pelvic relapse landscapes from patients who had experienced pelvic failure after conventional radical hysterectomy., Findings: 212 consecutive patients underwent TMMR without adjuvant radiation. 134 patients (63%) had high-risk histopathological factors. At a median follow-up of 41 months (5-110), three patients developed pelvic recurrences, two patients developed pelvic and distant recurrences, and five patients developed distant recurrences. Recurrence-free and overall 5-year survival probabilities were 94% (95% CI 91-98) and 96% (93-99), respectively. Treatment-related grade 2 morbidity was detected in 20 (9%) patients, the most common being vascular complications. Resection of the Müllerian compartment resulted in local tumour control irrespective of the metric extension of the resection margins. The pelvic topography of the peak relapse probability after conventional radical hysterectomy indicates an incomplete resection of the posterior subperitoneal and retroperitoneal extension of the Müllerian compartment., Interpretation: Resection of the embryologically defined uterovaginal compartment seems to be pivotal for pelvic control in patients with cervical cancer. TMMR without adjuvant radiation has great potential to improve the effectiveness of surgical treatment of early-stage cervical cancer., Funding: University of Leipzig, Leipzig, Germany.

Vaginal development has been a longstanding controversy, which hampers studies on vaginal diseases as well as cervical and uterine diseases. Most concerns center on: why is the vaginal epithelium different from the uterine epithelium; and where does the vagina originate from? It is commonly held that the rodent vagina has a dual origin: the cranial part is derived from the Mullerian duct (Mullerian vagina) and the caudal part derived from the urogenital sinus (sinus vagina). This concept was deduced from morphological observations. However, it cannot explain the difference between the Mullerian vagina and the uterus. Moreover, accumulating new data from genetic and molecular studies contradicts the urogenital sinus origin of the sinus vagina. The present review summarizes previous morphological observations and new findings from genetic and molecular studies, and addresses molecular mechanisms underlying the origin and organogenesis of the vagina in rodents. It provides evidence to show that the whole vagina is derived the Mullerian duct. BMP4 reshapes the intermediate mesoderm-derived Mullerian duct into the vaginal primordium. The latter thus exhibits different features from the uterus, including the stratified squamous epithelium and insensitivity to anti-Mullerian hormone. The sinus vagina is formed by extrinsic BMP4-mediated caudal extension of the Mullerian duct. The present review thus shows how a century of controversy over the origin and organogenesis of the vagina has been resolved. This new understanding will provide additional insight into genetic diseases and tumors of the female reproductive tract.

Purpose: Retrospective reviews suggest that the functional outcomes of surgery of the urogenital sinus have often been unsatisfactory and to our knowledge the long-term results of newer surgical techniques have yet to be evaluated. A precise understanding of pelvic fetal neuroanatomy is germane for optimizing surgical correction of the urogenital sinus., Materials and Methods: The pelves of 10 human female fetuses were serially sectioned. Masson's trichrome staining and immunochemistry for the neuronal marker S100 (Dako Corp., Carpinteria, California) along with anatomical computer reconstruction allowed 3-dimensional analysis of the nerves in relation to the pelvic structures as an animated motion picture., Results: Two types of neuronal structures were identified. 1) A dense perivisceral foil of branching nerves closely surrounded the pelvic organs. The localization of most nerves was on the external faces of the viscera with a limited fraction in the rectovaginal and urethrovaginal septa. This innervation was from the anterior cephalad periurethral area to the posterior caudal perirectal area. 2) A significant amount of nerves surrounded the cephalad urethra on its anterior and posterior faces., Conclusions: Based on these anatomical data during surgical repair of a urogenital sinus we would advocate minimal mobilization of the lateral faces of the vagina, avoiding dissection of the proximal urethra above the pubic bone and electing a vaginal flap in severe cases.

Human fetal bladder development starts in the 9th to 10th week of gestation. Smooth muscle cell formation is induced by Hedgehog proteins and their signaling in the surrounding mesenchyma of the fetal bladder cavity. Bladder wall thickness increases significantly with advancing gestation, mediated by linear growth patterns irrespective of the related sex. lt is the aim of this article to address new insights into bladder development to enhance our knowledge about normal and pathological conditions that occur when developmental processes are disturbed.

Objective: Current surgical treatment of cervical carcinoma is based on the assumption of undirected intra- and transcervical local tumor propagation and is executed by tailored excision of the paracervical tissues. We have recently demonstrated that cervical carcinoma spreads for extended phases during its malignant progression within the permissive compartment of the Müllerian morphogenetic unit (Lancet Oncol 2005;6:751-56) and proposed Müllerian compartment resection as the new principle for surgical treatment of cervical cancer. Do we need a new classification of radical hysterectomy?, Methods: The therapeutic index of the surgical treatment of cervical carcinoma FIGO stages IB1-IIB by extirpation of the Müllerian compartment through total mesometrial resection (TMMR) without adjuvant radiation is evaluated by an ongoing controlled prospective trial at the University of Leipzig., Results: From 7/1998 to 12/2006, 163 patients with cervical carcinoma, FIGO stages IB1 (n=94), IB2 (n=21), IIA (n=14) and IIB (n=34) have been treated with TMMR and nerve-sparing therapeutic lymph node dissection. Twenty-five patients received (neo)adjuvant chemotherapy. No patient underwent adjuvant radiotherapy although 95 patients (58%) would have needed this additional modality in case of conventional radical hysterectomy because of their high-risk histopathological tumor features. At a median follow-up time of 45 months (3-104 months), recurrence-free and disease-specific overall survival is 93% and 96%. Maximum treatment-related morbidity according to the Franco-Italian score has been grade 2 in 12 patients (8%)., Conclusions: The developmental view of local tumor spread and surgical anatomy holds a great promise for improving the therapeutic index of surgical cervical cancer therapy and challenges both the classification of radical hysterectomy based on tailored paracervical resection and the indication for adjuvant radiation.

Objective: To investigate if an asymmetry exists in the lateral distribution of obstructed hemivagina and renal agenesis in women with uterus didelphys., Design: All English-language medical papers on uterus didelphys, obstructed hemivagina, and associated renal agenesis published from 1980 to 2005 and identified by Embase, Medline, and Pubmed database searches were retrieved. In addition, 41 institutional cases are described. We considered articles in which the presence of a uterus didelphys, obstructed hemivagina, and renal agenesis was assessed as well as the affected side. Data were stratified based on surgical confirmation or imaging evidence of the specific müllerian anomaly. Two authors abstracted data independently on standardized forms, and the combined frequency of right- and left-side malformation subtype was computed., Result(s): Thirty-six reports including 138 subjects were selected. Unilateral hemato- or pyocolpos was on the right side in 91 patients (66%). Among the 125 cases with surgical demonstration of the müllerian malformation subtype, 81 (65%) had the anomaly on the right side. In the institutional series, lesions were on the right side in 25 cases (61%). Combining the above figures, the observed proportion of right-sided anomalies (116/179) was 65% (95% CI 57% to 72%)., Conclusion(s): Left-right asymmetry may be induced before organogenesis, establishing differences in morphogenesis on the left and right sides of the embryo.

Background: The existence of a longitudinal vaginal septum with double cervix communicating bilaterally with a nonseptate uterine body and normal adnexa is an unusual müllerian anomaly., Case: A 43-year-old woman presented with menorrhagia and duplication of the cervix and vagina. Afibromatous uterus was suggested by clinical examination and confirmed by ultrasonography. The patient underwent total abdominal hysterectomy with bilateral salpingooophorectomy. The surgical specimen revealed a fibromatous uterus with double cervix communicating bilaterally with a nonseptate uterine body; both adnexa were normal., Conclusion: This rare müllerian anomaly is inconsistent with the classical embryologic theory of caudal to cranial müllerian development but supports the alternative embryologic hypothesis suggested by Müller et al, according to which fusion and absorption begin at the isthmus and proceed simultaneously in both the cranial and caudal directions.