Primary Amenorrhea Due to Anatomical Abnormalities of the Reproductive Tract: Molecular Insight.

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, 17ß-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.

Animal Models and Alternatives in Vaginal Research: a Comparative Review.

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.

Extracellular matrix components and elasticity regulate mouse vaginal epithelial differentiation induced by mesenchymal cells†.

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 development of the human vaginal fornix and the portio cervicis.

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.

SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium.

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.

Testosterone and Vaginal Function.

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.

The embryology of persistent cloaca and urogenital sinus malformations.

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 4th and 7th 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 19th 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.

The embryology of persistent cloaca and urogenital sinus malformations / 亚洲男科学杂志(英文版)

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 4th and 7th 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 19th 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.

Peculiarities of prenatal vagina morphogenesis.

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: assessing the case for an anterior and posterior division.

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.

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct.

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.

Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina.

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.

New theory of uterovaginal embryogenesis.

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.

Comparison of inguinal hernia and asymptomatic patent processus vaginalis in term and preterm infants.

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.

[Pelvic inflammatory disease due to Herlyn-Werner-Wunderlich syndrome]. / Enfermedad inflamatoria pélvica causada por el síndrome de Herlyn-Werner-Wunderlich.

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.

ANTECEDENTES: el síndrome de Herlyn-Werner-Wunderlich es una malformación urogenital congénita que asocia un útero didelfo con un tabique vaginal longitudinal que forma una hemivagina ciega y agenesia renal ipsilateral a ésta. La presentación clínica es muy variable, lo que retrasa el diagnóstico y provoca algunas complicaciones que pueden ser graves. Caso clínico: paciente femenina de 13 años de edad, con diagnóstico de síndrome de Herlyn-Werner-Wunderlich a raíz de un cuadro de abdomen agudo por un absceso tuboovárico derecho. El tabique vaginal formaba una hemivagina ciega derecha microperforada que provocaba sangrados genitales intermitentes. Este hematocolpos se colonizó con microorganismos y el ascenso de estos a la cavidad pélvica causó el absceso tuboovárico derecho. La resonancia magnética nuclear aportó mayor información para el diagnóstico. La resección del tabique vaginal comunicó los dos hemiúteros con una sola vagina y los síntomas desaparecieron. CONCLUSIÓN: el síndrome de Herlyn-Werner-Wunderlich es poco conocido y puede manifestarse de forma atípica, lo que dificulta el diagnóstico y retrasa el tratamiento. Para evitar complicaciones irreversibles es importante mantener una alta sospecha clínica.

[Müllerian anomalies. Obstructed hemivagina and ipsilateral renal anomaly syndrome (OHVIRA)]. / Malformaciones müllerianas. Síndrome de hemivagina obstruida y anomalía renal ipsilateral (OHVIRA).

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.

Las malformaciones de los conductos de Müller son un grupo de entidades raras y poco diagnosticadas que ocasionan síntomas inespecíficos en adolescentes y pueden acompañarse de problemas de infertilidad y RESULTADOS obstétricos adversos. Estas malformaciones ocurren durante la gestación como consecuencia del desarrollo anormal de los conductos de Müller en diferentes etapas del proceso de formación del aparato reproductor femenino. El síndrome de hemivagina obstruida y anomalía renal ipsilateral, antes conocido como el síndrome de Herlyn-Werner-Wünderlich, es un padecimiento poco común, caracterizado por útero didelfo con una hemivagina obstruida por un tabique vaginal, y la asociación de una anomalía renal (agenesia renal principalmente) ipsilateral a la obstrucción. Este síndrome rara vez se identifica durante la niñez y se vuelve sintomático posterior a la menarquia, ocasionado por los síntomas obstructivos. A veces se identifica posterior a la evaluación de una paciente con problemas de infertilidad o pérdidas gestacionales recurrentes. El diagnóstico clínico es difícil, por eso se requieren estudios de imagen en los que el ultrasonido y la resonancia magnética desempeñan un papel decisivo para el diagnóstico, clasificación y plan terapéutico. El diagnóstico y tratamiento oportunos logran la desaparición de los síntomas, con pronóstico reproductivo adecuado, y se evitan las principales complicaciones: endometriosis, adherencias pélvicas e infertilidad. OBJETIVO: mostrar la fisiopatología, las manifestaciones clínicas, los métodos diagnósticos y terapéuticos del síndrome de hemivagina obstruida y anomalía renal ipsilateral.

The developmental origin of cervical and vaginal epithelium and their clinical consequences: a systematic review.

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.

Duplicated uterus and hemivaginal or hemicervical atresia with ipsilateral renal agenesis: an institutional clinical series of 52 cases.

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.

Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium.

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.