development, it is also possible for only one mullerian duct to develop, giving rise to a single uterine horn (unicornuate uterus). unicornuate uteri commonly develop on the right side, although the reason for this preference remains elusive. the second stage of mullerian duct development involves the fusion of the inferior portion of the ducts to form the uterus, cervix and upper two-thirds of the vagina. the superior part of the mullerian ducts do not fuse and form the left and right fallopian tubes. disruptions to this stage of development can result in didelphys or bicornuate uteri anomalies. in both didelphys and bicornuate uteri, the non-fusion of the mullerian ducts results in two distinct uterine cavities. the third and final stage of mullerian duct development is septal resorption. after the lower mullerian ducts fuse, a central septum is left behind, and this partition must be eliminated to give rise to a single uterine cavity, cervical canal and vaginal canal. defects in septal resorption may produce a septate uterus or arcuate uterus, where the septum divides the uterine cavity. more than 50% of women with reported mullerian anomalies have septate uteri. it is common for other developmental defects to occur in conjunction with mullerian anomalies, including renal, skeletal, auditory and cardiac abnormalities. causes the causes of mullerian anomalies are not well-understood. the aetiology of this congenital disease may be multifactorial, with genetics, socioeconomic factors and geographic factors playing a role in dysfunctional mullerian duct development. mullerian anomalies likely occur early in development, as the congenital disorder often occurs in association with renal and anorectal disorders. typically, women with mullerian abnormalities have a normal female karyotype (46, xx). most incidences of mullerian anomalies occur sporadically, with instances of familial inheritance patterns being less common. the genetic component of the disease classically follows an autosomal dominant pattern, with variable rates of genotypic expression. wnt4 signalling 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. the wnt4 gene pathway promotes female sexual differentiation, while suppressing male sexual differentiation. mice lacking wnt4 display androgenisation, the presence of wolffian ducts and absence of mullerian ducts. this effect is mirrored in humans, where mutations in the wnt4 gene has been observed in mrkh syndrome patients, who display hyperandrogenism. mutations in wnt4 gene are not always present in individuals with mullerian anomalies or mrkh syndrome, but the wnt4 gene is the only gene that has been clearly implicated in mrkh. tp63 tp63 is a tumour protein encoded by the emx2 gene, which is expressed in uterine and vaginal epithelium. the tp63 protein is required for epithelial differentiation during mullerian duct development in utero, by promoting the transcription of particular genes. emx2 mutations result in incomplete mullerian fusion. some women with unicornuate uteri exhibit mutant emx2 and significantly decreased expression of tp63, implicating tp63 in the fusion stage of mullerian development. diethylstilbestrol (des) des is a synthetic non-steroidal estrogen that was used during 1940–1971, to prevent premature births, miscarriage and other pregnancy complications. the use of des was discontinued after it was established that approximately 69% of females who were exposed to des in utero had uterine abnormalities. des has been marked as a teratogen as it results in malformation of the embryo. des is more potent than steroidal estrogen and binds to cytosolic receptors after crossing the placenta. des is not metabolised as quickly as endogenous estrogen. des remains bound to cytosolic receptors for a longer period of time. the extended binding time of des and the subsequent prolonged activation of its cognate receptors has been suggested to disrupt mullerian development, resulting in uterine abnormalities. exposure to des induced multiple uterine abnormalities including constriction bands, hypoplasticity in the uterine cavity and irregular borders. females exposed to this teratogen in utero presented most commonly with a t-shaped uterus, resulting in increased rates of ectopic pregnancy, spontaneous abortions, and an overall increased risk of adverse pregnancy outcome. impact on fertility and pregnancy the incidence of individuals with mullerian anomalies is twice as high in the infertile population than in the fertile population. women who do experience some obstetric complications usually have trouble maintaining full-term pregnancy, rather than issues with conception. due to improper development of the uterus and fallopian tubes, pregnancies in women with mullerian anomalies could result in spontaneous abortions, preterm birth, intrauterine growth restriction, perinatal mortality, placental abruption and other malpresentations. advancements in the epidemiology of mullerian anomalies has resulted in earlier diagnosis and treatment. uterine obstructions can be surgically repaired or managed to result in successful perinatal outcomes. normal ovarian function is not interrupted in females with mullerian anomalies and women with the anomaly have been able to utilise assisted reproductive technologies and a gestational carrier to increase the chance of successful reproductive outcomes. maintaining pregnancy physiological changes that occur in conjunction with mullerian anomalies explain why some women with the disorder experience difficulties maintaining pregnancy. these physiological changes include compromised blood flow to the uterus, low uterine muscle mass and an insufficient cervix. an insufficient flow of blood to the uterus would compromise nutritional supply to the foetus and waste removal from the foetus, and this can explain the heightened occurrence of low foetal birth weight (intrauterine growth restriction) and spontaneous abortions in women with mullerian anomalies. women with anomalies such as didelphys and bicornuate uteri present with a decreased uterine size and subsequent lower muscle mass. 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 mullerian anomalies. the degree to which the mullerian anomaly impairs the reproductive potential of a woman varies between individuals, and is dependent on the type of anomaly and its severity. women with minor fusion defects such as arcuate uteri and septate uteri tend to have a lower risk of aversive pregnancy outcome, compared to patients with major fusion defects, such as unicornuate uteri, bicornuate uteri and didelphys uteri. females with severe agenesis and/or hypoplasia, such as in mrkh syndrome, have an increased chance of poor reproductive outcomes without surgical intervention. assisted reproductive technologies women with mullerian 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. compared to individuals with no uterine anomalies, women with mullerian anomalies exhibit no differences in number of follicles produced, number of oocytes retrieved, or levels of estrogen produced. the normal follicular function, oocyte population and estrogen levels in women with mullerian anomalies occurs as normal ovarian function is not compromised in the disease. 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. if an individual has a reduced likelihood of effective implantation, a gestational carrier can be appointed to increase the chance of a successful pregnancy. women that present with unicornuate uteri may have an increased risk of spontaneous abortions, premature labour and preterm delivery, while individuals with unicornuate uteri may be at risk of ectopic pregnancy. these risks can be minimised if assisted reproductive technologies are utilised. correcting the anomaly prior to commencing assisted reproductive technologies can increase the possibility of reproductive success by increasing the chance of implantation and reducing the likelihood of complications occurring after pregnancy occurs. 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.