Müllerian duct anomalies are those structural anomalies caused by errors in Müllerian duct development as an embryo forms. Factors contributing to them include genetics and maternal exposure to substances that interfere with fetal development.
Genetic causes of Müllerian duct anomalies are complicated and uncommon. Inheritance patterns can be autosomal dominant, autosomal recessive, and X-linked disorders. Müllerian anomalies can be part of a multiple malformation syndrome. Studies have estimated that Mullerian anomalies can affect between 4 percent and nearly 7 percent of the female population.
Müllerian anomalies occur as a congenital malformation of the Müllerian ducts during embryogenesis. The Müllerian ducts are also referred to as paramesonephric ducts, referring to ducts next to (para) the mesonephric (Wolffian) duct during foetal development. Paramesonephric ducts are paired ducts derived from the embryo, and for females develop into the uterus, uterine tubes, cervix and upper two-thirds of the vagina. Embryogenesis of the Müllerian ducts play important roles in ensuring normal development of the female reproductive tract. However, when defects in each of the three phases of embryogenesis occur, it results in specific structural malformations which are distinguished according to anatomy into seven classes based on the American Society for Reproductive Medicine (ASRM) classification system. Class I and II anomalies result from underdevelopment of the two separate primitive uterine, vaginal and cervical pockets due to an arrest of stage one of organogenesis, resulting in underdevelopment of both left and right primitive uterus (class I) or underdevelopment of one of the primitive uterus (class II). Class III and IV anomalies result from failure of midline fusion of the two separate primitive pockets due to an arrest of stage two of organogenesis. Class V and VI anomalies result from failure of degeneration of the midline due to an arrest at stage three of organogenesis. Class VII anomalies are malformations caused by Diethylstilbestrol (DES).
Vaginal agenesis (Mayer–Rokitansky–Kuster–Hauser syndrome) and class I anomalies
Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome is a class I developmental disorder of the Müllerian ducts where the vagina and uterus are underdeveloped or absent. Females with MRHK syndrome have normal chromosome pattern of 46,XX karyotype, with normal functioning ovaries and secondary sex characteristics. Females with MRKH are unable to carry a pregnancy due to a malformed uterus, but can have children via assisted reproduction. MRKH syndrome type 1 results when only reproductive organs such as vagina are affected (vaginal agenesis) and type 2 results when abnormalities develop in other parts of the body such as abnormal kidney formation (unilateral renal agenesis).
Causes MRKH syndrome occurs from an arrest in the embryonic development in the first phase of organogenesis, resulting in underdevelopment of one or both the left and right primitive uterus and vagina (agenesis). Specifically, an arrest in the development of the paramesonephric ducts at week seven of gestation is linked to MRKH syndrome. During embryological development of the first phase, two separate uterine, cervical and vaginal pockets develop, following which a transverse septum forms across the caudal aspect in the upper two thirds of the vagina, which will dissolve when the lower one third of the vagina (developed from the urogenital sinus) fuses with the upper two thirds. An arrest at this stage means midline fusion of pockets do not occur and subsequently are unable to develop into a whole uterus, cervix and vagina.
Changes in the sequences of DNA bases due to mutations in WNT3, HNF1b and LHX1 are decreased in people with MRKH. Mice with mutant alleles for Wnt4, Wnt5a, Wnt7a and Wnt9b display varying extents of Müllerian duct hypoplasia indicating these genes may cause MRKH-like phenotypes in humans. A commonly identified copy number variants (CNVs) deletion of 17q12 is present in both type 1 and type 2 MRKH patients. The deletion of 17q12 results in a loss of 2 specific genes, HNFB and LHX1 at position q12 on chromosome 17 which are linked to Müllerian anomalies. Most 17q12 deletions result from genetic mutations in people with no known history of MRHK syndrome in their family.
Clinical presentations and diagnosis Patients who have not reached puberty are asymptomatic and diagnosis is difficult at this stage as the vagina and uterus are not fully developed. Estrogenization during puberty will increase the size of the uterus and allow for accurate evaluation. Symptomatic patients will present with pain at the uterus area due to infections or abnormal vaginal bleeding with cyclical pelvic pain.
Clinical presentations of septate uterus Diagnosis of septate uterus is based on ultrasound findings of two endometrial cavities and a smooth contouring of the fundus. The septum separating both endometrial cavities is thin and may descend into the cervix and the vagina. An over extended septum can cause the cervix to be obstructed, allowing pathogens to infect the region resulting in pelvic pain due to inflammation of the cervix. The Müllerian duct can be partially obstructed or fully obstructed. In the case where the Müllerian duct is partially obstructed, a reduced cervix opening obstructs menstrual bleeding flow, causing prolonged menstrual bleeding (hypermenorrhea). When there is complete obstruction, patients will present with absence of menstruation (amenorrhea). For patients where the septum extends longitudinally, bleeding will persist when a tampon is used as there are two vaginal openings, and dyspareunia (pain during intercourse) is common.
Magnetic resonance imaging (MRI) is useful in detecting obstruction of the endometrium due to hematometra, which appears as cavitated uterine buds on images, and are unable to be detected by ultrasound. MRI provides three-dimensional information of both internal and external contours and can differentiate septate from bicornuate uterus and other complex anomalies.
Development defects in other tissues
Malformation of the Müllerian ducts in foetuses can result in exhibition of extragenital anomalies such as urological anomalies that includes unilateral renal agenesis, horseshoe kidneys or malformation of collecting ducts. Skeletal malformations which include congenital dislocation of the hip, malformations of the arms, foot, ribs, hemivertebrae in the lumbar spine and cervical spina bifida are associated with Müllerian anomalies. Mutations of homeobox genes HOXA10, HOXA11 and HOXA13 in uterus malformations are also responsible for renal and skeletal developmental anomalies. However, the mechanism of action of these genes has not been established.
Non-surgical treatment The Frank and Ingram procedure is a common non-operative procedure used to increase function of the vaginal via dilators. The method uses graduated dilators to progressively invaginate the mucosa to dilate the opening, increasing depth and functionality of the vaginal over time. The Ingram modification involves using a bicycle seat positioned between the legs allowing direct contact with the perineum creating pressure on the vagina. Thus, by applying pressure to the mucosa, a neovagina forms. It takes between four months up to several years for complete successful treatment.
Surgical treatment The McIndoe procedure uses a split-thickness skin graft from the patient where it is placed over an obturator and sewn at the ends to from a tube with one closed end. A transverse incision at the vaginal dimple and a small cavity is made at the level of the peritoneum by the surgeon. The skin graft and obturator are inserted into the vagina vault and secured to the labia minora. Synthetic skin grafts are also an alternative, eliminating the need for skin grafts from patients. The use of dilators post operation for three to six months is required to prevent contraction of the vagina. Complications include skin graft failure due to the formation of a hematoma beneath the graft, postoperative hematoma that prevents the graft from receiving adequate nourishment, rectal perforation and fistula formation. Patients with prior history of vaginal or perineal surgery have higher complication rates.
The Sigmoid vaginaplasty procedure uses a segment of the patient's sigmoid colon where one end is pulled down to form a neovagina while the other end is sealed forming a blind pouch. Complications include narrowing of the vaginal (stenosis) and weakening of pelvic floor muscles and ligaments which are unable to support the uterus (uterine prolapse). As the use of dilators are not required for sigmoid vaginoplasty, this treatment is favoured over the McIndoe procedure.
Diethylstilbestrol and class VII anomalies Diethylstilbestrol (DES) was a synthetic oestrogen supplement introduced in 1938 to decrease miscarriage in the first trimester by enhancing the oestrogen dependent follicular phase and implantation of blastocysts. DES is a known teratogen, by crossing the placenta DES disrupts organogenesis by disorganising uterine muscle layers causing maldevelopment of uterus and uterine tube junctions. This prevents normal columnar ciliated cell formation of the vaginal epithelium and reabsorption of vaginal glands. When absorbed, DES is broken down to produce a transient quinone-like reactive intermediate that alters normal gene function of HOX and WNT, affecting differentiation of Müllerian ducts. In utero DES exposure has additionally been linked to epigenetic changes responsible for uterine anomalies such as dysregulation of the homeobox gene HOXA10 by hypermethylation of HOXA10, altering long term expression of genes which controls uterine organogenesis.
DES is also an endocrine disrupting compound (EDC) which alters normal hormone responses required for reproductive tract development in foetuses. A dose–response association for DES has not been establish but an association with the time of exposure in utero suggest exposure to DES at a certain embryological stage leads to increase susceptibility to Müllerian anomalies.
Female foetuses exposed to DES in utero (DES daughters) have abnormalities in development in three areas of the Müllerian duct, namely of their uterus, cervix and vagina. DES uterine anomalies include hypoplastic uterus (small uterus), T-shaped uterine cavity and constrictions of the endometrial cavity. DES uterine anomalies vary in extent in different races, with foetuses of African American females being more prone to fibroids development during organogenesis. DES cervical and vaginal anomalies include hypoplasia, collar and hood malformation of the vagina and cervix and is seen in 20% of women exposed to DES.
Epidemiology The prevalence of vaginal agenesis or class I uterine anomalies is 1:5000 female live births globally. The most prevalent form of vaginal agenesis is Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome and results in congenital aplasia or hypoplasia of Müllerian derived structures. MRKH syndrome account for 5% to 10% of all Müllerian anomalies. While septate uterus or class II uterine anomalies account for 3% to 7% of all Müllerian anomalies. The prevalence of Müllerian anomalies also differs within the female population, occurring in 5.5% of the general population, 8% in sterile females and 13.3% in females with a history of miscarriage.
Pathogenesis