Müllerian anomalies
[6] 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 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.
[8] 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).
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.
[11] 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.
[15] 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.
MRI provides three-dimensional information of both internal and external contours and can differentiate septate from bicornuate uterus and other complex anomalies.
The Ingram modification involves using a bicycle seat positioned between the legs allowing direct contact with the perineum creating pressure on the vagina.
Complications include narrowing of the vaginal (stenosis) and weakening of pelvic floor muscles and ligaments which are unable to support the uterus (uterine prolapse).
[23] 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.
[24] DES is also an endocrine disrupting compound (EDC) which alters normal hormone responses required for reproductive tract development in foetuses.
[25] DES uterine anomalies vary in extent in different races, with foetuses of African American females being more prone to fibroids development during organogenesis.
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.
In males, the sex-determining region Y (SRY) gene on the Y chromosome suppresses Müllerian duct development, by initiating the production of anti-Müllerian hormone by the Sertoli cells of the testicle.
[8][29] The Müllerian ducts develop to give rise to the fallopian tubes, uterus, cervix and upper two-thirds of the vagina.
[29] If the formation of the Müllerian ducts is impaired or does not occur, this can give rise to uterine, cervical and/or vaginal hypoplasia or agenesis.
[28] It is common for other developmental defects to occur in conjunction with Müllerian anomalies, including renal, skeletal, auditory and cardiac abnormalities.
WNT4 is a gene that has a crucial role in embryonic development, particularly to ensure the normal formation of the female reproductive system, the kidneys and several endocrine organs.
Some women with unicornuate uteri exhibit mutant EMX2 and significantly decreased expression of TP63, implicating TP63 in the fusion stage of Müllerian development.
The extended binding time of DES and the subsequent prolonged activation of its cognate receptors has been suggested to disrupt Müllerian development, resulting in uterine abnormalities.
Due to improper development of the uterus and fallopian tubes, pregnancies in women with Müllerian anomalies could result in spontaneous abortions, preterm birth, intrauterine growth restriction, perinatal mortality, placental abruption and other malpresentations.
[40] Physiological changes that occur in conjunction with Müllerian anomalies explain why some women with the disorder experience difficulties maintaining pregnancy.
[38][40] Women with anomalies such as didelphys and bicornuate uteri present with a decreased uterine size and subsequent lower muscle mass.
[37][38] A diminished uterine capacity reduces the likelihood of the foetus reaching full-term development due to spatial constraints, explaining the higher rates of preterm births observed in women with Müllerian anomalies.
[41] Females with severe agenesis and/or hypoplasia, such as in MRKH syndrome, have an increased chance of poor reproductive outcomes without surgical intervention.
[31] Women with Müllerian anomalies often utilise assisted reproductive technologies such as in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI) and embryo transfer (ET), and/or a gestational carrier.
In patients with uterine anomalies, there may be a chance that the endometrial cavity can be compromised, such that implantation following IVF does not always lead to a successful pregnancy.
[38] A greater rate of successful pregnancies are observed in women with septate uteri when the septum is operated on prior to implantation of the embryo.
