View source for Paramesonephric duct

{{Short description|Paired ducts in the mammalian embryo in the primitive urogenital structures}}
{{Infobox embryology
| Name          = Paramesonephric duct
| Latin         = ductus paramesonephricus
| Image         = Gray1109.png
| Caption       = Paramesonephric ducts (labelled as Müllerian ducts) shown in a human [[fetus]] of eight and a half to nine weeks old.
| System        =
| CarnegieStage = 17
| Precursor     = [[Intermediate mesoderm]]
| GivesRiseTo   =
}}
The '''paramesonephric ducts''' (or '''Müllerian ducts''') are paired ducts in the [[embryonic development|embryonic]] [[development of the reproductive system]] of humans and other [[Placentalia|placental mammals]]. The ducts run down the lateral sides of the [[genital ridge]], and terminate at the [[sinus tubercle]] in the primitive [[urogenital sinus]].<ref>{{cite book|last=Lombardi|first=Julian|publisher=Springer US|year= 2012|title= Comparative Vertebrate Reproduction |page=77|isbn= 978-1-46154-937-6 |url= https://books.google.com/books?id=tXvjBwAAQBAJ&pg=PA77}}</ref> In humans they form in the [[embryo]] during the 6th week of [[gestational age]], before [[sexual differentiation]] takes place. In the differentiated female, the paramesonephric ducts develop into the [[Female reproductive system|reproductive tract]], that includes the [[fallopian tube]]s (oviducts), [[uterus]], [[cervix]], and the upper part of the [[vagina]].<ref name="Jia2025">{{cite journal |last1=Jia |first1=Shuai |last2=Zhao |first2=Fei |title=Decoding Müllerian Duct Epithelial Regionalization |journal=Molecular Reproduction and Development |date=February 2025 |volume=92 |issue=2 |article-number=e70018 |doi=10.1002/mrd.70018|pmc=11850963 }}</ref>

In the male-determined embryo, the [[testes]] produce two hormones responsible for masculinization – [[anti-Müllerian hormone]] (AMH), and [[testosterone]]. [[Sertoli cell]]s secrete AMH, during weeks six and seven, which causes the paramesonephric ducts to regress. In week eight [[Leydig cell]]s secrete testosterone which stimulates the formation of male genitals from the [[mesonephric duct]]s.<ref name="Moore2020">{{cite book |last1=Moore |first1=Keith L. |last2=Persaud |first2=T |last3=Torchia |first3=Mark |title=The developing human: clinically oriented embryology |date=2020 |publisher=Elsevier |location=Edinburgh ; New York |isbn=9780323611541 |page=245 |edition=Eleventh}}</ref>

Each paramesonephric duct is situated just lateral to each [[mesonephric duct]] (Wolffian duct). The mesonephric ducts are not completely useless in the female case: they secrete [[protein Wnt-9b]], which is necessary for the elongation of the paramesonephric ducts. Elongation also happens through the active migration of the paramesonephric epithelium, which happens through a [[phosphoinositide 3-kinase]] pathway.<ref>{{cite journal |last1=Wilson |first1=Danielle |last2=Bordoni |first2=Bruno |title=Embryology, Mullerian Ducts (Paramesonephric Ducts) |url=https://www.ncbi.nlm.nih.gov/books/NBK557727/ |website=StatPearls |publisher=StatPearls Publishing |date=2025 |pmid=32491659 }}</ref>

==Development==
[[File:2915_Sexual_Differentation-02.jpg|thumb|left|Schematic of [[sexual differentiation]] of the [[gonad]]s]]

The [[female reproductive system]] develops from two embryological segments: the urogenital sinus and the paramesonephric ducts. The two are conjoined at the [[sinus tubercle]].<ref>{{cite journal | author = Yasmin Sajjad | title = Development of the genital ducts and external genitalia in the early human embryo | journal = The Journal of Obstetrics and Gynaecology Research | volume = 36 | issue = 5 | pages = 929–937 | doi =10.1111/j.1447-0756.2010.01272.x| date =  2011-07-27 | pmid = 20846260 | s2cid = 27710882 }}</ref><ref name="Elsevier Saunders">{{cite book|last1=Moore|first1=Keith|last2=Persaud|first2=T|last3=Torchia|first3=Mark|title=The Developing Human: Clinically Oriented Embryology|date=2013|publisher=Elsevier Saunders|location=Philadelphia|isbn=978-1-4377-2002-0|pages=269–271|edition=9}}</ref> Paramesonephric ducts are present on the embryo of both sexes.<ref name="Elsevier Saunders"/><ref>{{cite journal |vauthors=Rey R, Grinspon R | title = Normal male sexual differentiation and aetiology of disorders of sex development | journal = Male Reproductive Endocrinology | volume = 25 | issue = 2 | pages = 221–238 | doi= 10.1016/j.beem.2010.08.013| date = 2011-07-27 | pmid = 21397195 }}</ref> Only in females do they develop into reproductive organs. They degenerate in males whereas the adjoining [[mesonephric duct]]s develop into male reproductive organs. The sex based differences in the contributions of the paramesonephric ducts to reproductive organs is based on the presence, and degree of presence, of [[anti-Müllerian hormone]].

=== Initial formation ===
During the [[development of the reproductive system]], the paramesonephric ducts are formed just lateral to the [[mesonephric ducts]] (formed earlier) in both female and male embryos 6 weeks after fertilization. A ribbon of thickened coelomic epithelium is selected by [[PAX2]], and in turn the [[Fibroblast growth factor|FGF]]s, and in turn [[LHX1]], to become the Müllerian surface epithelium (MSE).<ref name=Roly18>{{cite journal |last1=Roly |first1=Zahida Yesmin |last2=Backhouse |first2=Brendan |last3=Cutting |first3=Andrew |last4=Tan |first4=Tiong Yang |last5=Sinclair |first5=Andrew H. |last6=Ayers |first6=Katie L. |last7=Major |first7=Andrew T. |last8=Smith |first8=Craig A. |title=The cell biology and molecular genetics of Müllerian duct development |journal=WIREs Developmental Biology |date=May 2018 |volume=7 |issue=3 |article-number=e310 |doi=10.1002/wdev.310 |pmid=29350886 }}</ref> During this time, primordial [[germ cells]] migrate from the yolk sac to the [[genital ridge]], a region of [[mesenchyme]] running parallel with, and derived from, the [[mesonephros]].<ref name="Falcone">{{cite book |last1=Falcone |first1=Tommaso |last2=Hurd |first2=William W. |title=Clinical Reproductive Medicine and Surgery |url=https://books.google.com/books?id=fOPtaEIKvcIC&dq=uterovaginal+primordium&pg=PA173 |publisher=Elsevier Health Sciences |access-date=5 November 2022 |language=en |date=1 January 2007|isbn=978-0323033091 }}</ref> The Müllerian duct mesenchyme (MDM) is formed from the MSE and possibly the mesonephros; [[WNT4]] expression is required for this process.<ref name=Roly18/> The MDM also secretes [[WNT4]], which (together with other molecular factors) cause the craniocaudal invagination<ref name="Falcone"/> of the MSE. The invagination fuses into a duct, and the MSE becomes known as the Müllerian duct epithelium (MDE).<ref name=Roly18/>

The early duct is short and needs to elongate to reach the [[urogenital sinus]]. This is caused by [[WNT9B]] produced by the neighboring mesonephric ducts.<ref name=Roly18/>

By the time basic formation is complete, the duct's cross section consists of a central lumen, a layer of MDE, and a mass of MDM around it.<ref name=Roly18/> The MDE produces [[WNT7A]], which causes the MDM to produce [[AMHR2]], allowing AMH to take effect.<ref name=Roly18/> The caudal parts of the paramesonephric ducts fuse into a single tube, known as the '''uterovaginal primordium''', before flowing into the dorsal aspect of the [[urogenital sinus]] at the [[sinus tubercle]] directly medial to the [[mesonephric ducts]].<ref name="Falcone"/>

===Anti-Müllerian hormone===
{{Main|Anti-Müllerian hormone}}
The further development of the paramesonephric (Müllerian) ducts is controlled by [[anti-Müllerian hormone]] (AMH; also known as Müllerian-inhibiting substance, "MIF" for "Müllerian-inhibiting factor", "MIH" for "Müllerian-inhibiting hormone", or "APH" for anti-paramesonephric hormone).<ref>{{cite journal |vauthors=Ball B, Conley A, Grundy S, Sabeur K, Liu I | title = Expression of anti-Mullerian hormone (AMH) in the equine testis | journal = Theriogenology | volume = 69 | issue = 5 | pages = 624–631| date = 27 July 2011 | doi=10.1016/j.theriogenology.2007.11.009| pmid = 18242669 }}</ref><ref>{{cite book|last1=Minkoff|first1=Eli|last2=Baker|first2=Pamela|title=Biology Today: An Issues Approach|date=2004|publisher=Garland Science|location=New York|isbn=1136838759|page=296|edition=Third}}</ref>

{| class="wikitable"
| Male embryogenesis || The developing [[testes]] produce AMH causing regression of the paramesonephric ducts. || Disturbances can lead to [[persistent Müllerian duct syndrome]]. || The ducts disappear except for the vestigial [[vagina masculina]] and the [[appendix testis]].
|- 
| Female embryogenesis || The absence of AMH results in the development of the paramesonephric ducts into the [[uterine tubes]], [[uterus]], and the upper 2/3 of the [[vagina]]. || Disturbance in the development may result in uterine absence ([[Müllerian agenesis]]) or [[uterine malformation]]s. || The ducts develop into the upper [[vagina]], [[uterus]], and [[uterine tubes]].
|}

AMH is a [[glycoprotein]] hormone that is secreted by [[Sertoli cells]] (a type of [[sustentacular cell]]) in males as they begin their morphologic differentiation in response to [[SRY]] expression. AMH begins to be secreted around week 8, which in turn causes the paramesonephric ducts to regress very rapidly between the 8th and 10th weeks. However, small paramesonephric ducts can still be identified, and the remnants can be detected in the adult male, located in the [[appendix testis]], a small cap of tissue associated with the testis. Remnants of the paramesonephric ducts can also be found in the [[prostatic utricle]], an expansion of the prostatic urethra at the center of the [[seminal colliculus]].<ref name="Embryology"/> 

When AMH is present, it first activates [[AMHR2]] (AMH receptor-type II) expressed by the MDM (mesenchymal) cells surrounding the duct. The activation of AMHR2 causes the expression of "type 1" receptors, which include [[ACVR1]] (ALK2), [[BMPR1A]] (ALK3), or [[BMPR1B]] (ALK6). Both types I and II are required for the correct development of the male reproductive system. Collectively they initiate [[SMAD (protein)|Smad]] signaling and lead to the expression of apoptosis-encouraging metalloproteases.<ref name=Roly18/>
* In the absence of the Wnt7a within the duct epithelium as the ducts regress, ductal AMHR-II expression is lost, and residual paramesonephric ducts would be retained in males, throwing off the urogenital system.
* [[Cryptorchidism]] (undescended testis) or [[ectopic testis]] with [[inguinal hernia]]s have been identified in human males due to AMH and AMHR-II gene mutations.<ref name=Roly18/>
* When the type I receptors are blocked or knocked out in mice within the paramesonephric duct mesenchyme, AMH-induced paramesonephric duct regression is lost. However, some of the type I receptors can be compensated by another: Alk2 knockouts are normal, while half of Alk3 knockouts show failed regression similar to Amh null mutants.<ref name=Roly18/>

=== Non-AMH ===
When AMH is absent, regression does not occur. In this case, WNT7A from the MDE encourages the location-specific expression of [[HOXA10]] and [[HOXA11]], which specifies the development of the uterus and cervix, in the MDM. Two additional Hox genes, [[HOXA9|HoxA9]] and [[HOXA13|HoxA13]], specify the development of the Fallopian tube and the upper vagina. The expression of these Hox genes depend on [[WNT5A]] being expressed. [[WNT4]] remains required for further uterine development.<ref name=Roly18/>

==Function==
{{See also|Development of the reproductive system}}
[[File:Female reproductive tract epithelium types.jpg|thumb|Types of [[epithelium]] throughout [[female reproductive tract]]]]
In females, the paramesonephric ducts give rise to the fallopian tubes, uterus, and upper portion of the vagina, while the mesonephric ducts degenerate due to the absence of male androgens. In contrast, the paramesonephric ducts begin to proliferate and differentiate in a cranial-caudal progression to form the aforementioned structures. During this time, the single-layered paramesonephric duct epithelium differentiates into other structures, ranging from the ciliated columnar epithelium in the uterine tube to stratified squamous epithelium in the vagina.<ref name=Embryology>{{cite book|last=Schoenwolf|first=Gary C.|title=Larsen's Human Embryology|year=2008|publisher=Churchill Livingstone|isbn=9780443068119|pages=509, 510504, 518, 520}}</ref>

The paramesonephric ducts and the mesonephric ducts share a majority of the same mesenchyme due to Hox gene expression. The genes expressed play a critical role in mediating the regional characterization of structures found along the cranial-caudal axis of the female reproductive tract.

==Clinical significance==

===Mutations in AMH===
Individuals that are 46, XY and have been tested positive for mutations in their AMH or AMH receptor genes have been known to exhibit features typical of that which are exhibited in [[persistent Müllerian duct syndrome]] due to the fact that the paramesonephric ducts fail to regress. When this happens the individuals develop structures that are derived from the paramesonephric duct, and also structures that are derived from the mesonephric duct. A male that has [[persistent Müllerian duct syndrome]] may have an upper vagina, uterus, and uterine tubes as well as [[ductus deferens]] along with male external genitalia. The female organs are in the correct anatomical position but the position of the testis varies. 60% to 70% of detected cases, both testes will lie in the normal position for the ovaries; about 20% to 30% of the time, one of the testis will lie within the inguinal hernial sac while in other cases both testes will lie within the same inguinal hernia sac. However whenever an individual exhibits persistent Müllerian duct syndrome, the ductus deferens will run along the lateral sides of the uterus.<ref name="Embryology"/>

=== Paramesonephric duct anomalies===
Anomalies that develop within the paramesonephric duct system continue to puzzle and fascinate obstetricians and gynecologists. The paramesonephric ducts play a critical role in the female reproductive tract and differentiate to form the uterine tubes, uterus, superior vagina as well as the uterine cervix. Many types of disorders can occur when this system is disrupted ranging from uterine and vaginal agenesis to the duplication of unwanted cells of the uterus and vagina. Paramesonephric malformations are usually related to abnormalities of the renal and axial skeletal system.<ref name="Embryology"/> Malfunction in the ovaries and age onset abnormalities can also be associated with most paramesonephric ducts. Most often, abnormalities are recognized once the external genitalia is no longer masked and the internal reproductive organ abnormalities become revealed. Due to a very broad range of anomalies it is very difficult to diagnose paramesonephric duct anomalies.<ref name="Mullerian Duct Anomalies">{{cite web|last=Amesse|first=Ibrahim|title=Mullerian Duct Anomalies|url=http://emedicine.medscape.com/article/405335-overview|access-date=2012-11-29}}</ref>

Due to improved surgical instruments and technique, women with paramesonephric duct anomalies can have normal sexual relations. Through the use of Vecchietti and Mclndoe procedures, women can carry out their sexual activity.<ref name="Mullerian Duct Anomalies"/> On another note, many other surgical advances have tremendously improved fertility chances as well as obstetric outcomes. Assisted reproductive technology makes it possible for some women who have paramesonephric duct anomalies to conceive and give birth to healthy babies.

==History==
They are named after [[Johannes Peter Müller]], a [[physiologist]] who described these ducts in his text "Bildungsgeschichte der Genitalien" in 1830.

== See also ==
* [[Defeminization]]
* [[Prostatic utricle]]
* [[Sexual differentiation]]

==References==
{{Reflist}}

==External links==
* {{EmbryologyUNC|genital|010}}
*[https://web.archive.org/web/20110217005015/http://www.aboutkidshealth.ca/En/HowTheBodyWorks/SexDevelopmentAnOverview/SexualDifferentiation/Pages/DuctDifferentiation.aspx How the Body Works/Sex Development/Sexual Differentiation/Duct Differentiation] - [[The Hospital for Sick Children, Toronto|The Hospital for Sick Children (GTA - Toronto, Ontario, Canada)]]
* [http://emedicine.medscape.com/article/273534-overview Müllerian Duct Anomalies]
* [http://www.britannica.com/EBchecked/topic/396903/Mullerian-duct Müllerian duct]


{{Sex determination and differentiation}}
{{Development of urinary and reproductive systems}}
{{Authority control}}

[[Category:Embryology of urogenital system|Muellerian duct]]
[[Category:Vagina]]
[[Category:Eponyms in biology]]