Talk:Vagina Development

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Cite this page: Hill, M.A. (2021, July 23) Embryology Vagina Development. Retrieved from

10 Most Recent Papers

Note - This sub-heading shows an automated computer PubMed search using the listed sub-heading term. References appear in this list based upon the date of the actual page viewing. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. In comparison, references listed on the content page and discussion page (under the publication year sub-headings) do include editorial selection based upon relevance and availability. (More? Pubmed Most Recent)

Cervix Embryology

<pubmed limit=5>Cervix Embryology</pubmed>

Vagina Embryology

<pubmed limit=5>Vagina Embryology</pubmed>


ACOG Committee Opinion No. 728 Summary: Müllerian Agenesis: Diagnosis, Management, And Treatment

Obstet Gynecol. 2018 Jan;131(1):196-197. doi: 10.1097/AOG.0000000000002452.


Müllerian agenesis, also referred to as müllerian aplasia, Mayer-Rokitansky-Küster-Hauser syndrome, or vaginal agenesis, has an incidence of 1 per 4,500-5,000 females. Müllerian agenesis is cau0073ed by embryologic underdevelopment of the müllerian duct, with resultant agenesis or atresia of the vagina, uterus, or both. Patients with müllerian agenesis usually are identified when they are evaluated for primary amenorrhea with otherwise typical growth and pubertal development. The most important steps in the effective management of müllerian agenesis are correct diagnosis of the underlying condition, evaluation for associated congenital anomalies, and psychosocial counseling in addition to treatment or intervention to address the functional effects of genital anomalies. The psychologic effect of the diagnosis of müllerian agenesis should not be underestimated. All patients with müllerian agenesis should be offered counseling and encouraged to connect with peer support groups. Future options for having children should be addressed with patients: options include adoption and gestational surrogacy. Assisted reproductive techniques with use of a gestational carrier (surrogate) have been shown to be successful for women with müllerian agenesis. Nonsurgical vaginal elongation by dilation should be the first-line approach. When well-counseled and emotionally prepared, almost all patients (90-96%) will be able to achieve anatomic and functional success by primary vaginal dilation. In cases in which surgical intervention is required, referrals to centers with expertise in this area should be considered because few surgeons have extensive experience in construction of the neovagina and surgery by a trained surgeon offers the best opportunity for a successful result. PMID: 29266072 DOI: 10.1097/AOG.0000000000002452


New insights into human female reproductive tract development

Differentiation. 2017 Sep - Oct;97:9-22. doi: 10.1016/j.diff.2017.08.002. Epub 2017 Aug 11.

Robboy SJ1, Kurita T2, Baskin L3, Cunha GR3.


We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Müllerian epithelium and the lower 1/5th derived from urogenital sinus epithelium, while Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Müllerian ducts) cranially and squamous epithelium of urogenital sinus caudally. Since Müllerian and urogenital sinus epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer's proposal that human vaginal epithelium derives solely from urogenital sinus epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development.

PMID: 28918284

An earlier description gave the vagina arising by downward growth of the Wolffian and Mullerian ducts, with the sinovaginal bulbs located at the caudal ends of the Wolffian ducts. An earlier understanding was that the upper part of the vagina derived from Müllerian ducts and the lower part from the sinovaginal bulbs (formed by fusion form the vaginal plate) all derived from the urogenital sinus. The terms sinovaginal bulbs and vaginal plate were first coined by Koff in 1933.Koff AK. (1933). Development of the vagina in the human fetus. Contrib Embryol , 24, 59-91. PMID: 12332362

Molecular mechanisms of development of the human fetal female reproductive tract

Differentiation. 2017 Sep - Oct;97:54-72. doi: 10.1016/j.diff.2017.07.003. Epub 2017 Jul 29.

Cunha GR1, Kurita T2, Cao M3, Shen J3, Robboy S4, Baskin L3.


Human female reproductive tract development rests mostly upon hematoxilyn and eosin stained sections despite recent advances on molecular mechanisms in mouse studies. We report application of immunohistochemical methods to explore the ontogeny of epithelial and mesenchymal differentiation markers (keratins, homobox proteins, steroid receptors), transcription factors and signaling molecules (TP63 and RUNX1) during human female reproductive tract development. Keratins 6, 7, 8, 10, 14 and 19 (KRT6, KRT7, KRT8, KRT10, KRT14, KRT19) were expressed in a temporally and spatially dynamic fashion. The undifferentiated Müllerian duct and uterovaginal canal, lined by simple columnar epithelia, expressed KRT7, KRT8 and KRT19. Glandular derivatives of the Müllerian duct (uterine tube, uterine corpus and endocervix) maintained expression of these keratins, while tissues that undergo stratified squamous differentiation (exocervix and vagina) expressed KRT6, KRT14 and KRT10 during development in an age-dependent fashion. TP63 and RUNX1 were expressed prior to KRT14, as these two transcription factors are known to be upstream from KRT14 in developing Müllerian epithelium. In the vagina, KRT10, a marker of terminal differentiation, appeared after endogenous estrogens transformed the epithelium to a thick glycogenated squamous epithelium. Uroplakin, a protein unique to urothelium, was expressed only in the bladder, urethra and vaginal introitus, but not in the female reproductive tract itself. Mesenchymal differentiation was examined through immunostaining for HOXA11 (expressed in uterine mesenchyme) and ISL1 (expressed in vaginal mesenchyme). A detailed ontogeny of estrogen receptor alpha (ESR1), progesterone receptor (PGR) and the androgen receptor (AR) provides the mechanistic underpinning for the teratogenicity of estrogens, progestins and androgens on female reproductive tract development. Immunohistochemical analysis of differentiation markers and signaling molecules advance our understanding of normal development of the human female reproductive tract. These observations demonstrate remarkable similarities in mouse and human female reproductive tract development, but also highlight some key differences. KEYWORDS: Cervix; Estrogen receptor; Keratins; Müllerian duct; Uterovaginal canal; Uterus; Vagina PMID: 29053991 DOI: 10.1016/j.diff.2017.07.003

Identification and functional analysis of a novel LHX1 mutation associated with congenital absence of the uterus and vagina

Oncotarget. 2017 Jan 31;8(5):8785-8790. doi: 10.18632/oncotarget.14455.

Zhang W1,2,3, Zhou X4,5, Liu L4, Zhu Y1, Liu C6, Pan H3, Xing Q1, Wang J7, Wang X3, Zhang X4, Cao Y1, Wang B2,3.


Congenital absence of the uterus and vagina (CAUV) is the most extreme female Müllerian duct abnormality. Several researches proposed that genetic factors contributed to this disorder, whereas the precise genetic mechanism is far from full elucidation. Here, utilizing whole-exome sequencing (WES), we identified one novel missense mutation in LHX1 (NM_005568: c.G1108A, p.A370T) in one of ten unrelated patients diagnosed with CAUV. This mutation was absent from public databases and our internal database. Through the luciferase reporter analysis, we found that the mutation could change the transcriptional activity of LHX1 and its effect on the regulation of the downstream target gene GSC, which might be associated with urogenital system development. In short, we concluded that the LHX1 may be a pathogenic gene of CAUV. Our results demonstrate the power of whole exome sequencing and gene prioritization approach as diagnostic tools in clinical practice that help make genetic diagnosis of CAUV. KEYWORDS: LHX1; Müllerian duct abnormality; congenital absence of the uterus and vagina; transcriptional activity; whole exome sequencing

PMID 28061432 DOI: 10.18632/oncotarget.14455

See also 2014 paper Lhx1 is required in Müllerian duct epithelium for uterine development. PMID 24560999


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

Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14354-14359. Epub 2016 Nov 22.

Nakajima T1,2, Iguchi T1,3, Sato T4.


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. KEYWORDS: Müllerian duct; oviduct; retinoic acid; uterus; vagina

PMID 27911779 PMCID: PMC5167189 [Available on 2017-06-13] DOI: 10.1073/pnas.1608808113

Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract

Hum Mol Genet. 2016 Mar 15;25(6):1059-73. doi: 10.1093/hmg/ddv621. Epub 2015 Dec 31.

Prunskaite-Hyyryläinen R1, Skovorodkin I1, Xu Q1, Miinalainen I2, Shan J1, Vainio SJ3.


The Müllerian duct (MD) is the anlage of the oviduct, uterus and upper part of the vagina, the main parts of the female reproductive tract. Several wingless-type mouse mammary tumor virus (MMTV) integration site family member (Wnt) genes, including Wnt4, Wnt5a and Wnt7a, are involved in the development of MD and its derivatives, with Wnt4 particularly critical, since the MD fails to develop in its absence. We use, here, Wnt4(EGFPCre)-based fate mapping to demonstrate that the MD tip cells and the subsequent MD cells are derived from Wnt4+ lineage cells. Moreover, Wnt4 is required for the initiation of MD-forming cell migration. Application of anti-Wnt4 function-blocking antibodies after the initiation of MD elongation indicated that Wnt4 is necessary for the elongation as well, and consistent with this, cell culture wound-healing assays with NIH3T3 cells overexpressing Wnt4 promoted cell migration by comparison with controls. In contrast to the Wnt4 null embryos, some Wnt4(monomeric cherry/monomeric cherry) (Wnt4(mCh/mCh)) hypomorphic mice survived to adulthood and formed MD in ∼45% of cases. Nevertheless, the MD of the Wnt4(mCh/mCh) females had altered cell polarization and basement membrane deposition relative to the controls. Examination of the reproductive tract of the Wnt4(mCh/mCh) females indicated a poorly coiled oviduct, absence of the endometrial glands and an undifferentiated myometrium, and these mice were prone to develop a hydro-uterus. In conclusion, the results suggest that the Wnt4 gene encodes signals that are important for various aspects of female reproductive tract development. © The Author 2015. Published by Oxford University Press.

PMID 26721931 PMCID: PMC4764189 DOI: 10.1093/hmg/ddv621

This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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New theory of uterovaginal embryogenesis

Organogenesis. 2016 Jan 2;12(1):33-41. doi: 10.1080/15476278.2016.1145317. Epub 2016 Feb 22.

Makiyan Z1.


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. KEYWORDS: Mullerian theory; embryogenesis research, endometriosis aetiology, extra genital endometriosis; new theory about uterovaginal organogenesis; uterovaginal anomalies; uterovaginal organogenesis

PMID 26900909 PMCID: PMC4882121 DOI: 10.1080/15476278.2016.1145317

Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract

Hum Mol Genet. 2016 Mar 15;25(6):1059-73. doi: 10.1093/hmg/ddv621. Epub 2015 Dec 31.

Prunskaite-Hyyryläinen R1, Skovorodkin I1, Xu Q1, Miinalainen I2, Shan J1, Vainio SJ3.


The Müllerian duct (MD) is the anlage of the oviduct, uterus and upper part of the vagina, the main parts of the female reproductive tract. Several wingless-type mouse mammary tumor virus (MMTV) integration site family member (Wnt) genes, including Wnt4, Wnt5a and Wnt7a, are involved in the development of MD and its derivatives, with Wnt4 particularly critical, since the MD fails to develop in its absence. We use, here, Wnt4(EGFPCre)-based fate mapping to demonstrate that the MD tip cells and the subsequent MD cells are derived from Wnt4+ lineage cells. Moreover, Wnt4 is required for the initiation of MD-forming cell migration. Application of anti-Wnt4 function-blocking antibodies after the initiation of MD elongation indicated that Wnt4 is necessary for the elongation as well, and consistent with this, cell culture wound-healing assays with NIH3T3 cells overexpressing Wnt4 promoted cell migration by comparison with controls. In contrast to the Wnt4 null embryos, some Wnt4(monomeric cherry/monomeric cherry) (Wnt4(mCh/mCh)) hypomorphic mice survived to adulthood and formed MD in ∼45% of cases. Nevertheless, the MD of the Wnt4(mCh/mCh) females had altered cell polarization and basement membrane deposition relative to the controls. Examination of the reproductive tract of the Wnt4(mCh/mCh) females indicated a poorly coiled oviduct, absence of the endometrial glands and an undifferentiated myometrium, and these mice were prone to develop a hydro-uterus. In conclusion, the results suggest that the Wnt4 gene encodes signals that are important for various aspects of female reproductive tract development. © The Author 2015. Published by Oxford University Press.

PMID 26721931


The comprehensiveness of the ESHRE/ESGE classification of female genital tract congenital anomalies: a systematic review of cases not classified by the AFS system

Hum Reprod. 2015 May;30(5):1046-1058. Epub 2015 Mar 18.

Di Spiezio Sardo A1, Campo R1, Gordts S1, Spinelli M2, Cosimato C3, Tanos V1, Brucker S1, Li TC1, Gergolet M1, De Angelis C1, Gianaroli L1, Grimbizis G4.


STUDY QUESTION: How comprehensive is the recently published European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) classification system of female genital anomalies? SUMMARY ANSWER: The ESHRE/ESGE classification provides a comprehensive description and categorization of almost all of the currently known anomalies that could not be classified properly with the American Fertility Society (AFS) system. WHAT IS KNOWN ALREADY: Until now, the more accepted classification system, namely that of the AFS, is associated with serious limitations in effective categorization of female genital anomalies. Many cases published in the literature could not be properly classified using the AFS system, yet a clear and accurate classification is a prerequisite for treatment. STUDY DESIGN, SIZE AND DURATION: The CONUTA (CONgenital UTerine Anomalies) ESHRE/ESGE group conducted a systematic review of the literature to examine if those types of anomalies that could not be properly classified with the AFS system could be effectively classified with the use of the new ESHRE/ESGE system. An electronic literature search through Medline, Embase and Cochrane library was carried out from January 1988 to January 2014. Three participants independently screened, selected articles of potential interest and finally extracted data from all the included studies. Any disagreement was discussed and resolved after consultation with a fourth reviewer and the results were assessed independently and approved by all members of the CONUTA group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the 143 articles assessed in detail, 120 were finally selected reporting 140 cases that could not properly fit into a specific class of the AFS system. Those 140 cases were clustered in 39 different types of anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: The congenital anomaly involved a single organ in 12 (30.8%) out of the 39 types of anomalies, while multiple organs and/or segments of Müllerian ducts (complex anomaly) were involved in 27 (69.2%) types. Uterus was the organ most frequently involved (30/39: 76.9%), followed by cervix (26/39: 66.7%) and vagina (23/39: 59%). In all 39 types, the ESHRE/ESGE classification system provided a comprehensive description of each single or complex anomaly. A precise categorization was reached in 38 out of 39 types studied. Only one case of a bizarre uterine anomaly, with no clear embryological defect, could not be categorized and thus was placed in Class 6 (un-classified) of the ESHRE/ESGE system. LIMITATIONS, REASONS FOR CAUTION: The review of the literature was thorough but we cannot rule out the possibility that other defects exist which will also require testing in the new ESHRE/ESGE system. These anomalies, however, must be rare. WIDER IMPLICATIONS OF THE FINDINGS: The comprehensiveness of the ESHRE/ESGE classification adds objective scientific validity to its use. This may, therefore, promote its further dissemination and acceptance, which will have a positive outcome in clinical care and research. STUDY FUNDING/COMPETING INTERESTS: None. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. KEYWORDS: ESHRE/ESGE system; Müllerian anomalies; classification; complex anomaly; comprehensiveness

  • three systems have been proposed for the classification of female genital tract anomalies: that of the American Fertility Society (AFS), now the American Society of Reproductive Medicine system (AFS, 1988); the embryological–clinical classification system of genito-urinary malformations (Acién et al., 2004a; Acién and Acién, 2011); and the Vagina, Cervix, Uterus, Adnexa and associated Malformations (VCUAM) system, based on the Tumor, Nodes, Metastases principle in oncology (Oppelt et al., 2005).

PMID 25788565


Novel immunohistochemical data indicate that the female foetal urethra is more than an epithelial tube

Ann Anat. 2013 Dec;195(6):586-95. doi: 10.1016/j.aanat.2013.09.004. Epub 2013 Oct 16.

Pechriggl EJ1, Bitsche M, Blumer MJ, Zwierzina ME, Fritsch H.


The female urethra has often been neglected in previous studies on the development of the human urogenital system. Our aim has been to reach a consensus on the organogenesis of the female urethra and the vagina with respect to interactions between the epithelia with different evolutionary origins. Therefore we tried to clarify open questions on the spatiotemporal distribution of molecular markers raised against mesenchymal and epithelial structures within the developing human female urethra. Furthermore, we draw comparisons regarding gender-specific aspects in urethral development. To this effect, we used molecular markers such as different cytokeratins (CKs), p63, Ki67, uroplakin III, E-cadherin, vimentin, smooth muscle actin (SMA), cleaved caspase 3 and paired box gene 2 (PAX 2) to phenotype developmental changes. Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) assay was additionally performed to reveal apoptosis. We examined different gestational stages starting from week (W) 8 until W 15. Immunohistochemistry showed a distinct staining pattern for p63 and CK17, both markers for stem cells, ensuing from the urogenital sinus (UGS) proceeding into the Muellerian duct (MD). This was observed throughout development and might be a stimulus for the formation of the vaginal anlagen that derive from the MD. In the attachment area of the MD we detected a conglomeration of cells with different embryonic origins. The epithelium of the UGS became transitional at W 9 after fertilization, and the differentiation advanced in a cranial to caudal direction. The paraurethral glands showed a slightly different staining profile than the urethral epithelium, which may be able to explain why carcinomas of these structures display various histological appearances. In addition, we could show that during the development of the female urogenital system the primary incidence is the formation of the urethra. This is followed by the establishment of the vagina, which clearly depends on the proper differentiation of the UGS/urethra. Copyright © 2013 Elsevier GmbH. All rights reserved. KEYWORDS: CK17; Female urethral development; PAX2; Uroplakin III; p63

PMID 24172012 DOI: 10.1016/j.aanat.2013.09.004

Development of epithelial and mesenchymal regionalization of the human fetal utero-vaginal anlagen

J Anat. 2013 Apr;222(4):462-72. doi: 10.1111/joa.12029. Epub 2013 Feb 13.

Fritsch H1, Hoermann R, Bitsche M, Pechriggl E, Reich O.


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.

PMID 23406280


Normal and abnormal epithelial differentiation in the female reproductive tract

Differentiation. 2011 Oct;82(3):117-26. doi: 10.1016/j.diff.2011.04.008. Epub 2011 May 25.

Kurita T. Source Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.


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.

PMID 21612855

Vaginal microbiome of reproductive-age women

Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4680-7. Epub 2010 Jun 3.

Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO, Brotman RM, Davis CC, Ault K, Peralta L, Forney LJ.

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.


The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities clustered into five groups: four were dominated by Lactobacillus iners, L. crispatus, L. gasseri, or L. jensenii, whereas the fifth had lower proportions of lactic acid bacteria and higher proportions of strictly anaerobic organisms, indicating that a potential key ecological function, the production of lactic acid, seems to be conserved in all communities. The proportions of each community group varied among the four ethnic groups, and these differences were statistically significant [χ(2)(10) = 36.8, P < 0.0001]. Moreover, the vaginal pH of women in different ethnic groups also differed and was higher in Hispanic (pH 5.0 ± 0.59) and black (pH 4.7 ± 1.04) women as compared with Asian (pH 4.4 ± 0.59) and white (pH 4.2 ± 0.3) women. Phylotypes with correlated relative abundances were found in all communities, and these patterns were associated with either high or low Nugent scores, which are used as a factor for the diagnosis of bacterial vaginosis. The inherent differences within and between women in different ethnic groups strongly argues for a more refined definition of the kinds of bacterial communities normally found in healthy women and the need to appreciate differences between individuals so they can be taken into account in risk assessment and disease diagnosis.

PMID 20534435

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Search pubmed: Mullerian ducts


Developmental origin of vaginal epithelium

Differentiation. 2010 Sep-Oct;80(2-3):99-105. doi: 10.1016/j.diff.2010.06.007. Epub 2010 Jul 17.

Kurita T1.

Abstract 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.

Comment in Derivation of vaginal epithelium finally resolved: broader implications regarding mechanism and pathogenic considerations. [Differentiation. 2010] PMID 20638775


Revisiting old vaginal topics: conversion of the Müllerian vagina and origin of the "sinus" vagina

Cai Y. Int J Dev Biol. 2009;53(7):925-34. Review. PMID: 19598112 | IJDB


"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."

Fetal development of the female external urinary sphincter complex: an anatomical and histological study

Sebe P, Fritsch H, Oswald J, Schwentner C, Lunacek A, Bartsch G, Radmayr C. J Urol. 2005 May;173(5):1738-42; discussion 1742. PMID: 15821572


Experimental contributions to the study of the embryology of the vagina

Sánchez-Ferrer ML, Acién MI, Sánchez del Campo F, Mayol-Belda MJ, Acién P. Hum Reprod. 2006 Jun;21(6):1623-8. Epub 2006 Feb 13.

BACKGROUND: Acién's hypothesis, deduced from patients with malformations of the female genital tract, especially those with renal agenesis and ipsilateral blind hemivagina, affirms the embryology of the human vagina as deriving from the Wolffian ducts and the Müllerian tubercle and could explain the embryological origin of all the female genital malformations reported. In this study, we investigated the hypothesis in rats.

METHODS: Twenty-five pregnant rats were used to analyse female embryos (64) from day 15 (stage indifferent) to day 20 postcoitum (vagina completely formed). We performed transverse and longitudinal sections of embryos, haematoxylin-eosin tinction and immunohistochemical staining using markers specific to Wolffian derivatives. We also analysed the presence of these markers in the vagina of four adult rats.

RESULTS: The Müller ducts converge until they fuse into one tube, but caudally they diverge and finally they fuse with the 'urogenital sinus bulbs' that are actually the distal portion of the Wolffian ducts according to the immunohistochemical marking with GZ1 and GZ2. The Müllerian tubercle is observed between those elements. Then, the immunohistochemical staining can be seen all along the completely formed vagina, which is also observed in the vagina of the adult rat.

CONCLUSION: We prove the participation of Müller tubercle and Wolffian ducts in the formation of the vagina in rats, so we confirm experimentally Acién's hypothesis about the human vagina embryology.

PMID: 16476676

Lifetime changes in the vulva and vagina

Farage M, Maibach H. Arch Gynecol Obstet. 2006 Jan;273(4):195-202. Epub 2005 Oct 6. Review. PMID: 16208476

"The morphology and physiology of the vulva and vagina change over a lifetime. The most salient changes are linked to puberty, the menstrual cycle, pregnancy, and menopause. The cutaneous epithelia of the mons pubis, labia, and clitoris originate from the embryonic ectoderm and exhibit a keratinized, stratified structure similar to the skin at other sites. The mucosa of the vulvar vestibule, which originates from the embryonic endoderm, is non-keratinized. The vagina, derived from the embryonic mesoderm, is responsive to estrogen cycling. At birth, the vulva and vagina exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina acquire mature characteristics in a sequential fashion in response to adrenal and gonadal maturation. A trend to earlier pubertal onset has been observed in Western developed countries. In women of reproductive age, the vaginal mucosa responds to steroid hormone cycling, exhibiting maximal thickness and intracellular glycogen content at mid-cycle. Vulvar skin thickness remains unchanged but menstrual cycle-associated changes in ortho- and parakeratosis occur at the cytological level. The vulva and vagina further adapt to the needs of pregnancy and delivery. After menopause, tissue atrophy ensues. Post-menopausal changes in skin barrier function, skin hydration, and irritant susceptibility have been observed on exposed skin but not on the vulva. Nevertheless, older women with incontinence are at increased risk for developing incontinence dermatitis. A combination of factors, such as tissue atrophy, slower dissipation of excess skin hydration, shear forces associated with limited mobility, and lower tissue regeneration capacity increase the risk of morbidity from incontinence dermatitis in older women."

Baseline dimensions of the human vagina

Barnhart KT, Izquierdo A, Pretorius ES, Shera DM, Shabbout M, Shaunik A. Hum Reprod. 2006 Jun;21(6):1618-22. Epub 2006 Feb 14. PMID: 16478763

magnetic resonance imaging (MRI) to quantify distribution of a vaginal gel. Seventy-seven MRI scans were performed on 28 women before gel application to establish baseline vaginal measurements. Average dimensions were calculated for each woman and for the population. The influence of potential covariates (age, height, weight and parity) on these dimensions was assessed. ...Mean vaginal length from cervix to introitus was 62.7 mm. Vaginal width was largest in the proximal vagina (32.5 mm), decreased as it passed through the pelvic diaphragm (27.8 mm) and smallest at the introitus (26.2 mm)."


New concepts on the development of the vagina

Shapiro E, Huang H, Wu XR. Adv Exp Med Biol. 2004;545:173-85. Review. No abstract available. PMID: 15086027

Fetal development of the female external urinary sphincter complex: an anatomical and histological study

Sebe P, Fritsch H, Oswald J, Schwentner C, Lunacek A, Bartsch G, Radmayr C. J Urol. 2005 May;173(5):1738-42; discussion 1742. PMID: 15821572

  • Helper function of the Wolffian ducts and role of androgens in the development of the vagina. Drews U. Sex Dev. 2007;1(2):100-10. PMID: 18391520
"Here experiments with the complete androgen receptor defect in the testicular feminisation (Tfm) mouse are reported which show that the vagina is formed by caudal migration of Wolffian and Müllerian ducts. The cranial ends of the Wolffian ducts successively regress while the Müllerian ducts fuse to form the vagina. Immunohistochemistry of the androgen receptor reveals that the caudal ends of the Wolffian ducts remain in the indifferent stage and therefore have been mistaken as sinuvaginal bulbs. The Wolffian ducts do not contribute to the vagina itself but have a helper function during downward movement of the vaginal bud in the female. In the male the caudal ends serve as androgen operated switch for the negative control of vaginal development. The results indicate that the rudimentary vagina in the complete androgen insensitivity syndrome (CAIS) corresponds to non obliterated caudal ends of the Müllerian ducts. Selective atresia of the vagina in the MRKH (Mayer-Rokitansky-Kuster-Hauser) syndrome may be explained by the failure of Wolffian and Müllerian ducts to descend caudally"


Preliminary Note on the Development of the Clitoris, Vagina, and Hymen

J Anat Physiol. 1896 Oct;31(Pt 1):18-28.11.

Hart DB.

PMID: 17232227

PMCID: PMC1327808

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome

text and table below from

Surgical creation of a neovagina A number of techniques are appropriate for the correction of vaginal agenesis and there is no consensus regarding the best option, the approach being most often based on the surgeon's experience. Three methods are currently in use:

- The Abbe-McIndoe operation: this involves the dissection of a space between the rectum and the bladder, placement of a mold covered with a skin graft into the space, and diligent postoperative vaginal dilatation. Modifications of this procedure rely on spontaneous epithelialization or on the use of different materials such as peritoneum [111], minora labia grafting, or synthetic materials [112,113].

- The Vecchietti operation is a mixture of surgical and nonsurgical methods. It has been performed frequently in Europe over the last 20 years [70]. This procedure involves the creation of a neovagina via dilatation with a traction device attached to the abdomen, sutures placed subperitoneally by laparotomy, and a plastic olive placed in the vaginal dimple. A laparoscopic or celioscopic modification is often preferred and leads to comparable results [114].

- Sigmoidal colpoplasty: this technique involves vaginal replacement or creation of a neovagina by grafting a 12–18 cm long segment of sigmoid [115], providing that a single and/or left pelvic kidney does not impair the procedure. Sigmoidal colpoplasty is believed to be an efficient procedure giving excellent results, although complete adequacy for coital function often requires prolonged care and support [116].

Summary of differential diagnosis between MRKH syndrome and isolated vaginal atresia, WNT4 syndrome, and androgen insensitivity syndrome.
Isolated vaginal atresia
WNT4 syndrome
Androgen insensitivity
Upper vagina
Masculinized ovary
Breast development
Pubic-hair development
46, XX
46, XX
46, XX
46, XY
Morcel et al. Orphanet Journal of Rare Diseases 2007 2:13   doi:10.1186/1750-1172-2-13

Complex malformations of the female genital tract. New types and revision of classification. Acién P, Acién M, Sánchez-Ferrer M. Hum Reprod. 2004 Oct;19(10):2377-84. Epub 2004 Aug 27. PMID: 15333604


The development of the human vagina

BULMER D. J Anat. 1957 Oct;91(4):490-509. No abstract available. PMID: 13475148 | PMCID: 1244904

Development of the vagina in the human fetus

Contrib Embryol. 1933 Sep;24(140):59-91.

Koff AK.

Abstract PIP: Lack of uniformity of opinions concerning the development of the vag ina prompted an investigation into the successive stages of the vagina's developmental events. Observations on the material studied indicated: 1) that the upper part of the vagina develops from the mullerian ducts: 2) the lower part of the vagina is formed from the urogenital sinus in an area fromerly occupied by the mullerian tubercle; it is here that the hymen forms; 3) the hymen is formed passively by the invagination of the posterior wall of the sinus attributed to expansion of the vagina's lower end and; 4) formation of the vagina occurs without the participation of the wolffian ducts which involute at 50mm and usually rapidly and entirely disappear from the genital cord. These observations suggest that a caudocranial process occurs in which epithelial cells in the center of the solid cord undergo involution, desquamate and are discharged in part of the hymenal opening thus forming the vaginal canal. PMID 12332362

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