**3. Physiopathology**

166 A Bird's-Eye View of Veterinary Medicine

have been breed with success previous to the diagnosis, albeit the number of puppies in the litter is usually remarkably small comparing to the normal for the breed (Romagnoli & Schlafer, 2006; McIntyre et al., 2010). Sporadically, vulvar discharge, excessive vulvar licking and attraction of the male have been described (Kyles et al, 1996; Tsumagari et al., 2001).

The aim of this study was to discuss embryology, the gross anatomic features, clinical signs and implications, and available diagnostic approaches in cases of Müllerian duct anomalies.

Non-development or non-fusion (partial or complete) of Müllerian ducts may result in a variety of anomalies ranging from complete agenesis to duplication of female reproductive

In different clinical reports, a tendency for the use of different classifications for a common defect was found. Also, it is frequently found similar defects named distinctly for different species, in which develop with different patterns. These are indicative of the necessity of adopting a more uniform nomenclature. In an attempt to clarify the nomenclature used in this review, and to allow the easy identification of underlying major causes for a given defect, table 1 presents the classification for the anatomical congenital defects of the uterine-

Main cause Malformation Classification

Complete *Uterus unicornis* 

Segmental aplasia of the body or the cervix Longitudinal septation of the uterine body\* *Uterus didelphus\** 

Segmental stenosis or aplasia of the vagina (Also named vestibulo-vaginal constriction) Longitudinal septum in the cranial vagina\* Imperforate hymen\*

Segmental aplasia of the uterus (uni or bilateral)

Incomplete

Failure of segments of Müllerian ducts to develop

Failure of the caudal parts of the two Müllerian ducts to fuse appropriately and develop a single lumen

Failure of caudal ends of the Müllerian ducts to fuse with invaginated urogenital sinus thus impairing the establishment of anatomical continuity

Table 1. Classification of developmental abnormalities of the uterine-vaginal segment in

**2. Classification** 

organs (Moore & Persaud, 2008).

vaginal segment in dogs.

Failure in organogenesis

> Failure in fusion

\* Out of the scope of this review

dogs according to underlying malformations.

Many vertebrates share a common genetic system for embryonic patterning that includes the reproductive tract. To better understand the uterus and vagina congenital anomalies we will first discuss the normal tubular genitalia development.

Normal development of the female reproductive tract involves a series of highly orchestrated, complex interactions that direct differentiation of the Müllerian ducts and urogenital sinus to form the internal female reproductive tract. This dynamic process is completed throughout mechanisms of differentiation, migration, fusion, and canalization. In the indifferent stage both male and female embryos have 2 sets of paired genital ducts (Mcgeady et al., 2006): Wolffian (mesonephric) and the Müllerian (paramesonephric). Differentiation of the Wolffian ducts occurs earlier in the male embryo, and persists after the mesonephros disintegrates (Noden & de Lahunta, 1985; Moore & Persaud, 2008). The female differentiation occurs in a later gestational age, and is characterized by regression of the Wolffian ducts due to absence of masculinisation influences from the gonads, and by stabilization of the Müllerian ducts, which is estrogen sensitive in a precise window of time (Moore & Persaud, 2008). Estrogens block the development of the Müllerian ducts if applied before the differentiation began, or cause hypertrophy of the differentiated portion and prevented further differentiation of the ducts in more caudal regions, when applied afterwards (Dood & Wibbels, 2008).

The funnel-shaped cranial region of each paramesonephric duct remains open (communicating with the coelomic cavity) and will form the uterine tube. Postnatally the communication persists from the peritoneal cavity to the exterior (exclusively in females). Caudal to this, each duct develops into an uterine horn. The bilateral paramesonephric ducts caudal portion shift medially and fuse into a single tube. The paired Müllerian ducts, initially separated by a septum, fuse and form a single Y-shaped tubular structure, the uterovaginal primordium (UVP). UVP becomes the uterine body, uterine cervix, and the cranial third of the vagina. Uterine morphology varies significantly in mammals, due to different degrees of fusion of the distinct Müllerian ducts (Noden & de Lahunta, 1985; Moore & Persaud, 2008).

Normal vaginal development requires the fusion of components that derive from 2 embryologic structures: the mesodermal Müllerian ducts and the endodermal urogenital sinus (UGS). To achieve this fusion the bilateral blind ending paramesonephric ducts enter in contact with UGS. This contact promotes the cellular proliferation of the endoderm from the urogenital sinus and the formation of the vaginal plate. The vagina is derived from both the vaginal plate and the fused ends of paramesonephric ducts (Mcgeady et al., 2006). The cranial one-third comes from fused paramesonephric ducts and the caudal two-thirds

Congenital Aplasia of the Uterine-Vaginal Segment in Dogs 169

with some muscle strands (McIntyre et al., 2010) that frequently fail to present a lumen. As the contralateral uterine horn and the other genital segments retain patency, fluid accumulation does not occur unless the female develop cystic endometrial hyperplasia (CEH)/pyometra or other situations of segmental aplasia in the contralateral uterine horn are present (Figure 1A). The non-patent uterine horn may induce fluid accumulation in the

Due to a common embryologic origin, this malformation might co-exist with ipsilateral tubal and renal agenesis (Chang et al., 2008). Although this situation is described with more frequency in cats than in dogs, on its survey McIntyre et al. (2010) found a relative lower frequency of 28% in cats than 45.5% in dogs. Co-existence of renal agenesis appears also on older reports on *uterus unicornis* in female beagles in research colonies (Höfliger, 1971, cited by McEntee, 1990). As those animals were euthanized after the end of the experiments (they integrated the control groups), at young ages, clinical signs were absent. Often the abnormality is detected only at necropsy or surprises the surgeon during the surgery. In contrast, due to a different embryologic origin, most frequently both ovaries are found (Romagnoli & Schlafer, 2006; McIntyre et al., 2010). Other congenital defects besides kidney agenesis were found in animals bearing unicornuate uterus: ectopic contralateral ureter,

absent ipsilateral suspensory ligament and umbilical hernia (McIntyre et al., 2010).

Acquired diseases found in described conditions of unicornuate uterus include CEH of the contralateral uterine horn and polycystic ovaries. According to the descriptions, the later could correspond to cystic proliferation of the rete or the cranial uterine tube

In cases of segmental aplasia, whether its location may be at the uterine horns, body or cervix, frequently the anomalies are grossly visible as missing segments or strictures that interrupt the normal anatomy of the uterine-vaginal segment, and that correspond to failure of the development of all the layers of that segment, which are often reduced to a streak cord-like rudiment. However, in few situations the external layers of the Müllerian duct derivates (serosal and muscle layers) are properly differentiated, but the inner layers (mucosal and sub-mucosal layers) do not differentiate (Moore & Persaud, 2008). This is more often found in the vagina than the uterus. In practical terms, the potential deleterious effects over the reproductive potential and the occurrence of secondary diseases are similar

As the situation usually remains undiagnosed in young animals that maintain regular reproductive activity, the normally developed portion cranial to the atresia is distended due to fluid accumulation (Figure 1D to 1H). Distension of the uterine tube (Figure 1F) is possible (McIntyre et al., 2010). Primary lesions at the endometrium are rarely reported, but CEH may develop in older animals. However, due to excessive mucous fluid pressure of the ongoing mucometra, with time reduction in the thickness of the uterine walls and compression and attenuation of the endometrial glands is commonly found (McIntyre et

Segmental aplasia of the uterine horns may develop at any point of the structure (Figure 1A, 1C and 1G) (Schlafer & Miller, 2007; McIntyre et al., 2010), with segmental agenesis being

irregularly distributed for different segments of the uterine horns.

oviducts that distend (Figure 1C).

(Güvenc et al., 2006).

in the two situations.

al., 2010).

**4.2 Segmental aplasia of the uterus** 

originate from the vaginal plate. Degeneration of the center of the vaginal plate creates the vaginal lumen. A hymen may persist where the vagina joins urogenital sinus although in most domestic species it tend to disappear before puberty. The urogenital sinus forms the vestibule (Noden & de Lahunta, 1985; Moore & Persaud, 2008).

Apart from some remnants of the excretory tubes and a small portion of the mesonephric duct, with varying importance according to the species, all the female mesonephric derivates atrophies (Moore & Persaud, 2008).

The cause and heritability of congenital abnormalities in dogs remain undetermined (McIntyre et al., 2010). With exception for the situations accompanying intersex conditions, the karyotype is normal. We are unaware if the condition develops in consequence of genetic, endocrine, or environmental influences. Neither it is known if it might be associated to failure of the gonad or the mesonephros development (which absence may co-exist with the *uterus unicornis*), to failure in local gene expression or, in the case of a segmental aplasia, if it might be determined by disruption of the blood supply to the affected segment (Ribeiro et al., 2009; McIntyre et al., 2010).

A *unilateral uterine aplasia* (also termed unicornuate uterus) develops when one paramesonephric duct fails to develop; this results in a uterus with one uterine horn (Moore & Persaud, 2008). The kidney and the paramesonephric ducts have the same embryologic origin therefore this anomaly is usually associated with ipsilateral kidney absence (Chang et al., 2008). Unilateral uterine aplasia has been reported in dogs and cats (Schulman & Bolton, 1997; Pinto Filho et al., 2001; Güvenç et al., 2006). However, the ovary is of a separate embryological origin and is usually present (Moore & Persaud, 2008; Thode & Johnston, 2009).

Development defects of the Müllerian duct system may cause *segmental aplasia* in several portions of the Müllerian duct system. Partial or complete fusion or occlusion of one uterine horn, of the body of the uterus, or of the most caudal segments, such as the cervix and cranial vagina, may cause fluid accumulation cranially to the occlusion (McEntee, 1990; Oh et al., 2005; Romagnoli & Schlafer, 2006; Almeida et al., 2010; McIntyre et al., 2010). Failure of canalization of the vaginal plate results in atresia (blockage) of the vagina, originating a *transverse vaginal stenosis* or a segmental aplasia, which is found between the middle and the caudal third of the vagina (Schlafer & Miller, 2007). Isolated vaginal atresia is an extremely rare finding.

Given the many variables that are involved in the female genital tract differentiation and growth, the pathogenesis for each anomaly may be multifactorial and hence of difficult identification (McIntyre et al., 2010).
