Uterus Development

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Paramesonephric ducts.jpg

Contents

Introduction

Human fetal uterus growth
Johannes Müller (1801 - 1858)

This page introduces the uterus as part of the internal female reproductive tract development. Two paramesonephric ducts form from coelomic epithelium extending beside the mesonephric ducts. In the absence of Mullerian Inhibitory Factor these ducts proliferate and grow extending from the vaginal plate on the wall of the urogenital sinus to lie beside the developing ovary. The paired ducts begin to fuse from the vaginal plate end, forming the primordial body of the uterus and the unfused lateral arms form the uterine tubes. Recent research points to the paramesonephric ducts also being the entire embryonic origin of the vagina.


Johannes Peter Müller (1801 - 1858) in 1830 was the first to describe the duct historically named after him, the "Müllerian duct". The current terminology is the "paramesonephric duct".


Genital Links: Introduction | Lecture - Medicine | Lecture - Science | Online Practical | Primordial Germ Cell | Meiosis | Female | Ovary | Oocyte | Uterus | Vagina | Male | Testis | Spermatozoa | Prostate | Genital Movies | Abnormalities | Assisted Reproductive Technology | Puberty | Category:Genital
Historic Embryology: 1912 Urinogenital Organ Development | 1921 Urogenital Development | 1921 External Genital Development | Historic Disclaimer


Menstrual Cycle Links: Introduction | Menstrual Cycle - Histology | Ovary | Oocyte | Uterus | Uterine Gland | Estrous Cycle | Pregnancy Test | Implantation

Some Recent Findings

  • The origin of the Mullerian duct in chick and mouse[1] "In vertebrates the female reproductive tracts derive from a pair of tubular structures called Mullerian ducts, which are composed of three elements: a canalised epithelial tube, mesenchymal cells surrounding the tube and, most externally, coelomic epithelial cells. ... We show that all Mullerian duct components derive from the coelomic epithelium in both species. Our data support a model of a Mullerian epithelial tube derived from an epithelial anlage at the mesonephros anterior end, which then segregates from the epithelium and extends caudal of its own accord, via a process involving rapid cell proliferation. This tube is surrounded by mesenchymal cells derived from local delamination of coelomic epithelium."
  • Essential roles of mesenchyme-derived beta-catenin in mouse Mullerian duct morphogenesis[2]

Paramesonephric Duct

The Müllerian duct (= paramesonephric duct, preferred terminology) paired ducts that form the epithelial lining of female reproductive organs: utererine tube, uterus, upper vaginal canal. The term "paramesonephric" duct means beside the mesonephric (Wolffian) duct, which is its anatomical location in early development. Mullerian refers to Johannes Peter Müller (1801-1858) a German scientist who specialised in comparative anatomy. These ducts initially form and then degenerate in the male.

A recent study using both chicken and mouse embryos has shown that these initially paired tubular structures derive from the coelomic epithelium.[3]

"Müllerian epithelial tube derived from an epithelial anlage at the mesonephros anterior end, which then segregates from the epithelium and extends caudal of its own accord, via a process involving rapid cell proliferation. This tube is surrounded by mesenchymal cells derived from local delamination of coelomic epithelium."

Mullerian ducts have three elements:

  1. a canalised epithelial tube
  2. mesenchymal cells surrounding the tube
  3. coelomic epithelial cells


Duct Molecular Development

The paired paramesonephic ducts (Müllerian ducts) go through a series of developmental changes recently identified as regulated by a number of molecular factors.

Initiation

Coelomic epithelium Lim1 expressing cells are specified to a duct fate.[4]

  • Lim - proteins named for 'LIN11, ISL1, and MEC3,' are defined by the possession of a highly conserved double zinc finger motif called the LIM domain.
    • LIM domain-binding factors - interact with the LIM domains of nuclear proteins are capable of binding to a variety of transcription factors.

Invagination

Duct invagination induced by Wnt4 to reach the mesonephric (Wolffian)

Elongation

Cells at the leading tip proliferate and form the duct elongating to reach the cloaca (urogenital sinus). Mesonephric secretes WNT9b to guide duct elongation. Pax2 also acts in elongation and duct maintenance.

  • WNT9b - member of the WNT protein family that encode cysteine-rich secreted glycoproteins that act as extracellular signaling factors.
  • Pax2 - member of the paired box protein family.


Links: OMIM - WNT9b | OMIM - Pax2 | OMIM - paired box gene


Uterine Development Movie

Anterior view of development of the female uterus and vagina between Week 9 and 20.

The paramesonephric ducts (red) fuse in the midline to form the genital canal.

The urogenital sinus (yellow), in contact with the paramesonephric duct, thickens to form the sinusal tubercle which extends as a solid vaginal plate, then becomes hollow as the sinovaginal bulb, finally forming the vagina.


Development Overview

Urogenital indifferent.jpg Urogenital female.jpg
Common
Female
Internal Genital Tract Differentiation
Mullerian Duct (paramesonephric) - blue
(This historic image mislabels the vaginal origin)

The data below gives an overview of the timecourse of embryonic human uterine development.[5]

Carnegie stage 18 - Mullerian duct to the coelomic cavity was formed as the result of an invagination of the coelomic epithelium - stage 18
Carnegie stages 19 - 23 - duct grows independently from the invagination - stage 19
Week 20 - uterine horn fimbrial development begins and continues after birth - second trimester


Fetal Uterus

Paramesonephric ducts.jpg Paramesonephric duct.jpg
Urogenital sinus of female human embryo of eight and a half to nine weeks old (From model by Keibel) (Image: Gray's Anatomy) (Image modified from: Drews U, Sulak O, Schenck PA. Androgens and the development of the vagina.Biol Reprod. 2002 Oct;67(4):1353-9. PMID: 12297555)

Fetal Uterus Growth

Fetal uterus growth.jpg
Graph shows the growth during the fetal period of the uterus between week 19 and 38.[6] During this time the uterine circumferunce increases from about 20 mm to just under 60mm and the width increases from less than 10mm to just over 20 mm.

Uterine horn fimbrial development begins after week 20 and continues after birth.

Uterine growth continues postnatally, increasing outer muscle thickness and cyclic changes in the lining with puberty.

Adult external uterine orifice to the fundus is approximately 6.25 cm.

Newborn Uterus

Newborn uterus.jpg

Uterine Tubes

Adult Human right uterine tube and ovary
Developing Uterus (cat) showing relationship to ovary and degenerating mesonephros.

The unfused portion of the paramesonephric ducts will form the uterine tubes. Note that there are several synonyms used for the paired uterine tubes or Fallopian tubes or oviducts or uterine horns.

In the adult, the uterine tube has been described in 4 anatomical regions.

  1. Infundibulum - funnel-shaped open end of the uterine tube with fimbriae (finger-like extensions), which are closely associated with the ovary. Opens into the peritoneal cavity (abdominal ostium, ostium abdominale)
  2. Ampulla - uterine tube with highly folded structure with plicae (mucosal folds) and secondary folds dividing the lumen, usual site for fertilization.
  3. Isthmus - narrow portion of the uterine tube with fewer mucosal folds and a thick muscularis layer.
  4. Intramural - uterine tube which passes through the muscular wall of the uterus. (an alternative interpretation is that it is an extension of the body of the uterus)

Mucosa

  • formed by a ciliated and secretory epithelium resting on a very cellular lamina propria.
  • The number of ciliated cells and non-ciliated secretory cells varies along the oviduct.
  • Secretory activity varies during the menstrual cycle, and resting secretory cells are also referred to as peg-cells.
  • Some of the secreted substances are thought to nourish the oocyte and the very early embryo.

Muscularis

  • inner circular muscle layer and an outer longitudinal layer.
  • An inner longitudinal layer is present in the isthmus and the intramural part of the oviduct.
  • Peristaltic muscle action seems to be more important for the transport of sperm and oocyte than the action of the cilia.

Uterine Blood Supply

Gray1170.jpg


Uterine Glands

Uterine adenogenesis is the term used to describe the formation of uterine glands from the epithelial lining of the uterus. In mammals, this development occurs postnatally and has been described as occurring through a 3 step the sequence:

  1. differentiation and budding of the glandular epithelium.
  2. invagination and tubular coiling of the epithelium.
  3. branching of the glandular elements and their expansion throughout the endometrial stroma toward the myometrium.

Epithelial-mesenchymal interaction occurs through Wnt signalling during this process:

  • Wnt7a - expressed in the luminal epithelium
  • Wnt5a - expressed in the mesenchyme

In mice, this development sequence occurs between postnatal day (PND) 5 to 7 and involves Wnt up-regulation of Lymphoid Enhancing Factor 1 (Lef1).[7]

Links: Wnt | Epithelial Mesenchymal Interaction

Uterus Histology

See also Menstrual Cycle - Histology

Abnormalities

Uterine didelphys, obstructed hemivagina, and ectopic ureter on MR imaging in a 17-year-old girl.[8]
Uterine abnormalities.jpg A range of uterine and vaginal anatomical anomalies based upon the abnormal development and fusion of the paramesonephric ducts and vaginal plate development.

 

Unicornate uterus.jpg Unicornate Uterus - failure of the paramesonephric ducts to fuse. A single paramesomnephric duct has fused with the vaginal plate and now opens into the vagina, while the other forms a diverticulum.
Bicornuate uterus ectopic movie icon.jpg
 ‎‎Bicornuate Ectopic
Page | Play

Uterine Duplication

(uterus didelphys, double uterus, uterus didelphis) A rare uterine developmental abnormality where the paramesonephric ducts (Mullerian ducts) completely fail to fuse generating two separate uterus parts each connected to the cervix and having an ovary each.


Uterus/Vaginal

Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH, MRK anomaly, Rokitansky-Kuster-Hauser syndrome, RKH syndrome, RKH) consists of congenital aplasia of the uterus and the upper part of vagina due to anomalous development of Müllerian ducts, either isolated or associated with other congenital malformations, including renal, skeletal, hearing and heart defects. Has an incidence of approximately 1 in 4500 newborn girls and has been associated with a microdeletion at 17q12.[9]


Septate Uterus

Cervical: cervical agenesis, cervical duplication


Environmental Abnormalities

DES Diethylstilbestrol or diethylstilbetrol, is a drug that was prescribed to women from 1938-1971 to prevent miscarriage in high-risk pregnancies. The drug acted as a potent estrogen (mimics natural hormone) and therefore could also act as a potential endocrine disruptor. This led to a number of developing fetal reproductive tract and other abnormalities. In the female fetus, it increased risk of abnormal reproductive tract and also carcinogenic (cancer forming). In the male fetus, it increased the occurance of abnormal genitalia. The drug was banned by FDA (USA) in 1979 as a teratogen, it had previously also been used as livestock growth promoter and could have potentially entered the human food chain. (More? [endocrine2.htm Endocrine Abnormalities] | Abnormal Development - Drugs)


Links: Endocrine Abnormalities | Abnormal Development - Drugs | Childrens Hospital Boston - Congenital Anomalies of the Uterus | Medical Education Image Link - Cervical agenesis | OMIM - Rokitansky-Kuster-Hauser syndrome |

Broad Ligament

The broad ligament is found associated with the internal human female genital tract. It forms a mesentery consisting of a double fold of the peritoneum that connects the uterus to the peritoneal floor and walls.

Anatomically it has three parts:

  1. mesometrium - surrounding the uterus
  2. mesosalpinx - surrounding the uterine tube
  3. mesovarium - surrounding the ovary

Abnormalities include peritoneal endometriosis.

Gray1161.jpg

Molecular

Wnt genes - Wnt4, Wnt5a, and Wnt7a implicated in the formation and morphogenesis of the Müllerian duct.

Wnt7a - mediates the patterning of the oviduct and differentiation of the uterus.

beta-catenin - manufactured in the mesenchyme is a downstream effector of Wnt7a.

Bmp2 - decidualization regulator of gene expression and function (shown in mouse uterus).

Lim1, Lhx9, Emx, Pax-2, Hox-A9, Hox-A10, Hox-A11, Hox-A13, WT1, SF-1, GATA-4. TGF-beta


References

  1. Silvana Guioli, Ryohei Sekido, Robin Lovell-Badge The origin of the Mullerian duct in chick and mouse. Dev. Biol.: 2007, 302(2);389-98 PMID:17070514
  2. Erica Deutscher, Humphrey Hung-Chang Yao Essential roles of mesenchyme-derived beta-catenin in mouse Müllerian duct morphogenesis. Dev. Biol.: 2007, 307(2);227-36 PMID:17532316
  3. Silvana Guioli, Ryohei Sekido, Robin Lovell-Badge The origin of the Mullerian duct in chick and mouse. Dev. Biol.: 2007, 302(2);389-98 PMID:17070514
  4. Akio Kobayashi, William Shawlot, Artur Kania, Richard R Behringer Requirement of Lim1 for female reproductive tract development. Development: 2004, 131(3);539-49 PMID:14695376
  5. Ryozo Hashimoto Development of the human Müllerian duct in the sexually undifferentiated stage. Anat Rec A Discov Mol Cell Evol Biol: 2003, 272(2);514-9 PMID:12740945
  6. Development of the fetal uterus between 19 and 38 weeks of gestation: in-utero ultrasonographic measurements. Soriano D, Lipitz S, Seidman DS, Maymon R, Mashiach S, Achiron R. Hum Reprod. 1999 Jan;14(1):215-8. PMID: 10374123
  7. Shelton DN, Fornalik H, Neff T, Park SY, Bender D, et al. (2012) The Role of LEF1 in Endometrial Gland Formation and Carcinogenesis. PLoS ONE 7(7): e40312. doi:10.1371/journal.pone.0040312
  8. Zhen J Wang, Heike Daldrup-Link, Fergus V Coakley, Benjamin M Yeh Ectopic ureter associated with uterine didelphys and obstructed hemivagina: preoperative diagnosis by MRI. Pediatr Radiol: 2010, 40(3);358-60 PMID:19924410 | PMC2817805
  9. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports. Bernardini L, Gimelli S, Gervasini C, Carella M, Baban A, Frontino G, Barbano G, Divizia MT, Fedele L, Novelli A, Béna F, Lalatta F, Miozzo M, Dallapiccola B. Orphanet J Rare Dis. 2009 Nov 4;4:25. PMID: 19889212


Reviews

  • Lifetime changes in the vulva and vagina. Farage M, Maibach H. Arch Gynecol Obstet. 2006 Jan;273(4):195-202. PMID: 16208476
  • Function of sexual glands and mechanism of sex differentiation. Kavlock R, Cummings AJ Toxicol Sci. 2004 Aug;29(3):167-78. Review. PMID: 15467266 | See Related Articles

Articles

  • Essential roles of mesenchyme-derived beta-catenin in mouse Mullerian duct morphogenesis. Deutscher E, Hung-Chang Yao H. Dev Biol. 2007 May 3; PMID: 17532316
  • Hashimoto R. Development of the human Mullerian duct in the sexually undifferentiated stage. Anat Rec A Discov Mol Cell Evol Biol. 2003 Jun;272(2):514-9.

Search PubMed

Search May 2007 "embryonic uterine development" 3,025 reference articles of which 491 were reviews.

Search Pubmed: Uterus Development | embryonic uterine development | Paramesonephric Duct | Mullerian Duct | Endocrine Disruptors | uterine+adenogenesis

Additional Images

Terms

Note some of these terms relate to the maternal uterus during pregnancy.

  • cervical cerclage - A clinical birth procedure involving circumferential banding or suture of the cervix early (between 12 -14 weeks) or when required to prevent or treat passive dilation prior to completion of pregnancy (37 weeks), described as cervical insufficiency.
  • cervical insufficiency - (CI) A clinical term describing a painless and progressive dilatation and effacement of the cervix that may lead to second trimester abortions or preterm delivery. It has also been described as inability of the uterine cervix to retain a pregnancy in the absence of uterine contractions. The condition may in some instances treated clinically by cervical cerclage. The biological basis is currently undetermined with some evidence showing a genetic relationship.
  • cervical length - There is some data that shows the risk of spontaneous preterm labour and delivery increases in women who have a short cervix PMID 8569824.
  • cervical mucus plug - (CMP) During early pregnancy, maternal glands located at the cervical junction between vagina and uterus secrete mucus that forms a plug or barrier between these two structures.
  • cervical pregnancy - A rare type of ectopic pregnancy with implantation at the cervical canal, occurring with an incidence ranging between 1:1,000 and 1:18,000 pregnancies. Clinically, when an associated haemorrhage occurs a hysterectomy is usually performed.
  • cervical ripening - Clinical birth term describing the hormonal softening of the cervix to allow expansion in preparation for birth.
  • cervix - (Latin, cervix = neck) The female anatomical region of the uterus forming a canal that opens and connects to the vagina.
  • fundus - (Latin, fundus = "bottom") Top part of the uterus body lying between the two uterine tubes and a common implantation site.

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name.


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Cite this page: Hill, M.A. (2014) Embryology Uterus Development. Retrieved April 17, 2014, from http://embryology.med.unsw.edu.au/embryology/index.php?title=Uterus_Development

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Dr Mark Hill 2014, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G
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