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Embryology, Mullerian Ducts (Paramesonephric Ducts)
Danielle Wilson; Bruno Bordoni.
The Mullerian ducts are an essential aspect of the development of the urogenital system. Initially, they are present in both sexes but regress under the influence of Anti-Mullerian Hormone (AMH). This hormone is produced by the testes and serves to cease the development of female internal organs. Without the influence of AMH, the ducts develop into the uterus, uterine tubes, cervix, and the upper 1/3 of the vagina comprising some of the female internal genitalia. The function of these structures is the site of fertilization, and to transfer and support the egg throughout development. The development of the Mullerian ducts is highly regulated by different signaling molecules and gene expression, including include EMX2, HOXA13, PAX2, LIM1, and Wnt. Disruption of any of these can result in anomalies throughout development and present at birth. Examples of these anomalies include agenesis of the uterus, unicornuate uterus, bicornuate uterus, didelphys uterus, septate uterus, and arcuate uterus.<1><2>
There are three phases of the development of the Mullerian ducts. The phases are specification, invagination, and elongation. Throughout the initial phases of development, the Mullerian ducts have a close association with the Wolffian ducts. Thus before gonadal differentiation, both male and female embryo has two sets of ducts. The Wolffian ducts ultimately give rise to the male reproductive tract, the vas deferens, epididymis, and seminal vesicles. However, these ducts regress in an XX embryo due to the lack of testis-derived androgens. Mullerian ducts in the XY embryo regress due to the presence of testis-derived Anti Mullerian Hormone (AMH), which derives from the Sertoli cells of the testis. Without the presence of both testis-derived testosterone and AMH, the Mullerian ducts continue to develop into the female genitalia, including the fallopian tubes, uterus, cervix, and upper third of the vagina.<1><3><4>
Both the Mullerian and Wolffian ducts develop on the mesonephric kidneys. Mullerian duct precursors are present on the mesonephros in a specific region of the coelomic epithelium. This region has been referred to as the Mullerian ridge. The specification is the first step of Mullerian duct development and begins at the cranial pole of the mesonephric kidney. The Mullerian ducts are lateral and parallel to the Wolffian ducts at the cranial end. At the caudal end, the ducts cross ventrally, resulting in a location internal to the mesonephric duct. Next, the Mullerian surface epithelial (MSE) invaginate and proliferate caudally in the mesenchyme between the coelomic epithelium and Wolffian ducts; this forms the Mullerian duct mesenchyme (MDM). Then the invaginating MSE fuses with the Wolffian ducts to form the Mullerian duct epithelium (MDE). This structure is a canalized tube that will proliferate and migrate in a craniocaudal direction.<1><4>
Around gestational week 8, the terminal ends from both Mullerian ducts meet and join, forming the uterovaginal duct. This structure later develops into the fornix of the vagina. Then, the basement membrane of the two Mullerian ducts fuses. Around 12 weeks gestation, the basement membranes from the two Mullerian ducts disappear, creating the uterus. At this time, a septum separates the two Mullerian ducts. The septum later is resorbed through apoptosis. The Bcl2 gene may regulate this process. The distal end of the uterovaginal duct contacts the posterior wall of the urogenital sinus resulting in the Mullerian tubercle. Further, after the fusion of the distal ducts, the broad ligament of the uterus is formed by an extension of the peritoneal folds. The broad ligament connects the pelvic bone to the fused Mullerian ducts. The cranial end of the uterovaginal duct becomes the abdominal ostium of the fallopian tubes. The hymen appears to be formed by both the urogenital sinus and the Mullerian ducts.<4><5><6><3><7> The first observation of this formation was by JP Muller in 1830; the intermediate mesoderm forms Mullerian ducts.
The Mullerian duct is referred to as a mesoepithelial tube as it is not a true epithelial tube. It is derived from intermediate mesoderm and is composed of both epithelial and mesenchymal cells. The Mullerian ducts form from three tissue layers: MSE, MDM, and MDE. The MSE is the outermost layer, then the MDM, and the innermost the MDE. The MDE expresses a mesenchymal marker. However, the MDE does not also express typical epithelium markers until later in embryonic development. At later times, it will begin to express cadherin 1, which is a marker of a true epithelium.<1><4>
The interaction between the epithelium and the mesenchyme regulates transcription factors and signaling molecules necessary for the development of the Mullerian ducts. Some of the transcription factors include EMX2, HOXA13, PAX2, LIM1, and Wnt.Lim1(Lhx1) and Pax2 are essential in the specification of the Mullerian duct precursor cells. Specifically, Lim1 is necessary for the formation of the Mullerian duct epithelium. Without Lim1, agenesis of the Mullerian ducts occurs. Loss of Pax2 results in the absences of the kidneys and agenesis of the reproductive tract; this is due to the loss of the Wolffian and Mullerian ducts. Bmp/PAX2 and Fdf/LIM1 signaling regulate the initiation phase of Mullerian duct formation and are also necessary for specification. BMP signaling occurs in the cranial mesonephros and begins the expression of PAX2 in the MDM. The belief is that cells with PAX2 are prespecified Mullerian duct precursor cells. PAX2/BMP activates LIM1, which leads to the specification of the Mullerian ducts. Emx2 appears to be necessary for the formation of both the Mullerian and Wolffian ducts. Additionally, combination mutations in retinoic acid have shown malformations of the caudal portion of the reproductive tract. Lastly, invagination is regulated by fibroblast growth factor (Fgf).<1><8>
Wnt and Hox gene expression is also crucial for the development of the Mullerian ducts. Animal studies have shown that lack of Wnt7a leads to abnormal reproductive tracts in females, as it is a requirement for sexual dimorphic differentiation. Typical findings of Wnt7a dysfunction are a small, thin uterus that lacks typical uterine glands. The function of Wnt7a during embryonic development of the Mullerian ducts is to maintain the expression of Hoxa10 and Hoxa11. The expression of these two genes is important for the development of the Mullerian ducts. Hoxa10 determines the borders of tissues of the reproductive tract. Differentiation of the Mullerian ducts into structures of the female genitalia is also regulated by Hoxa genes, specifically Hoxa9, Hoxa10, Hoxa11, and Hoxa13. Wnt4 and WNT5a have also shown importance to the Mullerian ducts during later development. Absent Wnt4 causes abnormal uterine morphology, while absent WNT5a causes disruptions in the differential of the Mullerian Ducts caudally.<1><8><9>
The precursor cells of the Mullerian ducts express Lim1, which is a homeodomain transcription factor. Lim1 is essential for the formation and maintenance of the female reproductive tract. Missense mutations of Lim1 have been shown to result in agenesis of the Mullerian ducts. More recent specific studies have indicated that Lim1 is essential for the elongation of the Mullerian ducts, and loss of this gene leads to shortened fallopian tubes, aplasia of the uterus, and infertility.<1><9>
The influence of Wolffian ducts significantly affects the later stage of development of the Mullerian ducts. The association of these two structures is required for the correct elongation of the Mullerian ducts, while specification and invagination are independent of these structures. The influence of the Wolffian ducts contributes to the elongation of the Mullerian ducts. This process occurs through the secretion of a local signaling molecule that induces Mullerian duct cell proliferation. WNT9B is a Wolffian duct-derived factor that is necessary for the elongation of the Mullerian ducts. Further, researchers have observed the Mullerian duct to elongate through the proliferation and active migration of the MDE. These proliferating cells are located at the tip of the MDE and have a high proliferation index. This elongation uses the phosphatidylinositol 3-kinase signaling pathway, which is typically activated by tyrosine-kinase receptors.<1>
The function of the Mullerian ducts is to give rise to the organs that function in female reproduction.
In the male, these ducts will disappear through atrophy.
Anomalies in the female reproductive tract are estimated to be at 0.1 to 3.0% of live births. Because the Mullerian ducts originate from the same mesoderm as the mesonephros, any female reproductive tract anomaly should warrant investigation of renal anomalies. The typical investigation of Mullerian duct anomalies should start with a physical exam. However, the physical exam often is unrevealing. The initial imaging modality should be an ultrasound of the pelvis. Further investigation can be with an MRI, hysterosalpingography, or laparoscopy. The following are the classification of uterine anomalies found and other conditions related to the embryology of the Mullerian ducts.<8><5><6><2>
Class I: Uterine Agenesis/Hypoplasia
Uterine agenesis and hypoplasia are due to early developmental dysfunction of the Mullerian ducts around five weeks of gestation. This anomaly comprises 5 to 10% of all uterine abnormalities. Agenesis is defined as no identifiable uterus or identification of solely rudimentary tissue. This can present as primary amenorrhea with normal secondary sex characteristics during puberty. The secondary sex characteristics are due to fully developed ovaries. In uterine hypoplasia, there is a small but fully differentiated uterus.<10>
The most common form of uterine agenesis is Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). MRKH is an autosomal dominant condition with incomplete penetrance and variable expressivity. The incidence of MRKH has been estimated to 1 in 4500 female births. It is defined as agenesis of the uterus, cervix, and upper 1/3 of the vagina. Among the agenesis of these parts of the reproductive tract, individuals with MRKH can also have skeletal, renal, cardiac, auditory, and digital anomalies. There are two types of MRKH. Type 1 has agenesis of the uterus with two rudimentary horns and normal fallopian tubes. Type 2 is defined by either symmetric or asymmetric hypoplasia of the uterus with aplasia of one of the two horns, and fallopian tube malformations.<10><11>
Class II: Unicornuate Uterus
This condition is due to the arrest of the development of one of the Mullerian ducts. This anomaly accounts for 20% of all uterine anomalies. There are four different subtypes of the unicornuate uterus: absent rudimentary horn, non-cavitary rudimentary horn, cavitary communicating horn, and cavitary non-communicating rudimentary horn. The cavitary non-communicating rudimentary horn can cause obstruction, which can result in abdominal pain and ultimately need surgical intervention. Abnormal fetal presentation and intrauterine growth retardation are common obstetrical problems.<10><5>
Class III: Didelphys Uterus
Didelphys uterus is due to failure of fusion of the Mullerian ducts to form the uterus and accounts for 5% of uterine anomalies. In a didelphys uterus, each of the uterine horns fully develops due to the complete non-fusion of the Mullerian ducts. Two cervixes are present, and there is a deep fundal cleft. There can also be a transverse or longitudinal vaginal septum. There is no communication between the two uteruses. Spontaneous abortion and premature birth both increase due to this anomaly.<10><5>
Class IV: Bicornuate Uterus
A bicornuate uterus is due to the incomplete fusion of the Mullerian ducts. It is present in 10% of all uterine anomalies. This causes central myometrium, which can extend to the internal or external cervical os. A septum that extends to make two cervixes is referred to as a bicornuate bicollis uterus. The depth of the fundal cleft is greater than 1 cm. The horns are less functional in a bicornuate uterus than a didelphys uterus. Studies have shown little effect of the bicornuate uterus on obstetrical outcomes; however, there are better outcomes for partial bicornuate uterus than complete. Research has found the bicornuate uterus to have the highest rate of cervical incompetence among the Mullerian duct anomalies. Problems may present at menarche if an obstructive uterus didelphys is present. Pelvic adhesions and endometriosis are more prevalent in the obstructive anomaly.<10><5><2>
Class V: Septate Uterus
Septate uterus is the most common uterine anomaly, comprising 55% of anomalies. It is due to defective resorption of the fibrous septum between the two Mullerian ducts. The uterus divides into two cavities because of this septum. The septum can be composed of muscle, fibrous tissue, or both. Septate uteruses have the poorest obstetrical outcomes with spontaneous abortion rates of up to 94% and premature birth rates of up to 33%. The treatment for the septate uterus is a surgical intervention to remove the septum.<10><5>
Class VI: Arcuate Uterus
An arcuate uterus is due to the indention of the endometrium into the uterine fundus. An arcuate uterus is due to the near-complete but not total resorption of the uterine septum. There is limited data on the effect of an arcuate uterus on the obstetrical outcome.<10><5>
Class VII: Diethylstilbestrol (DES) Exposure
DES is a nonsteroidal estrogen analog that causes altered Hox gene expression in the Mullerian Ducts. DES affects newborn girls after their mothers used DES to prevent miscarriage. However, the research found that DES caused uterine malformations and increased the risk of vaginal clear cell carcinoma. Studies have shown that 69% of women exposed to DES have uterine anomalies. The typical uterine malformations include a hypoplastic uterus, a T-shaped uterine cavity (31%), abnormal transverse ridges and hoods, and cervical anomalies (44%). There is an associated two times increased risk of spontaneous abortion and a nine-fold increased risk of ectopic pregnancy for women exposed to DES. Further, there is an association with DES and an increase in premature labor and cervical incompetence.<1><10><5>
The Gartner duct is a remnant of the Wolffian duct; this can become a cystic structure in the lower wall of the vagina and is known as the Gartner’s cyst.<4>
Congenital anomalies of the Fallopian Tubes
These anomalies are rare and are typically agenesis, hypoplasia, or segmental narrowing of the fallopian tubes.<5>
Transverse Vaginal Septum
A transverse vaginal septum is present when there is a defect in the canalization of the vaginal plaque at the location of the urogenital sinus meeting the Mullerian duct. Variations are present in this type of septum, including perforation. A perforated transverse vaginal septum typically causes fewer symptoms as the patient can menstruate. The location of the septum determines the severity and treatment. The easiest to treat is the transverse septum that is thin, located low, and perforated. The most difficult is a high and thick septum. This type can present with a rectovaginal fistula and require a hysterectomy.<6>
Hand-Foot-Genital Syndrome (HFG)
HFG is an autosomal dominant condition due to mutations in the Hoxa13 gene. Patients with this disorder have shortened thumbs and great toes, and a bicornuate or didelphys uterus.
Persistent Mullerian Duct Syndrome (PMDS)
Alterations present in AMH secretion, AMH gene, or AMH receptors result in retained Mullerian ducts. Complete gonadal dysgenesis in males causes no secretion of AMH, while a mutation in the AMH gene or the AMH receptor causes abnormal function of AMH. The normal function of AMH in males is to bind to Type I and II receptors present in the MDM; this causes signal transduction via SMAD phosphorylation. Activation of the receptors results in apoptosis of the MDE in males. PMDS is an autosomal recessive disorder in males caused by a mutation in gene coding the AMH type II receptor. There have been 38 identified mutations that can cause this syndrome. Some of the mutations cause changes to the C terminal of the receptor rendering it bio-inactive. The non-functional AMH receptor leads to the retention of the Mullerian ducts in males. Normal findings at birth for a patient with PMDS include normal phenotype and cryptorchidism (unilateral or bilateral). The persistent Mullerian structures are typically discovered during surgical repair of the cryptorchidism.<1><12><13><7>