Female Reproductive System and Mammary Gland*

Sex Chromosome Disorders of Sexual Development: True chromosomal DSD is very rare. Cases of X_ (Turner syndrome) and XXY (Klinefelter syndrome) are reported. They usually have gonadal dysgenesis and a feminine phenotype.

Chimerism is more common. Chimeras and mosaics have two or more somatic cell types, each with a different chromosomal constitution. Chimeras have two genetically distinct cell types that come from different individuals, whereas mosaicism is a different chromosomal constitution from altered mitosis. The most common chimera in domestic animals is the freemartin calf (Fig. 18-3). Vessels of the placentas from two different fetuses fuse and exchange blood between fetuses. Each fetus becomes a hematopoietic chimera. Anastomosis of placental vessels occurs most often in bovine species and less frequently in other ruminants and pigs. The freemartin is the female of a set of male and female twins. Gene products from the cells of the male fetus induce fetal Sertoli cells and seminiferous cordlike structures in the ovaries of the female twin. The ovaries are small and can have reduced number of or no germ cells or organs partially converted to testes. The paramesonephric (Müllerian) duct derivatives vary from almost normal to cordlike structures, but their lumens do not communication with the vagina. The vagina, vestibule, and vulva are hypoplastic. Vesicular glands are always present; other mesonephric (Wolffian) structures are present to varying degrees. Externally, the animal has a female phenotype, but the vestibule and vagina are short, the vulva is hypoplastic, and the clitoris is enlarged. The male twin is minimally affected.

XY Disorders of Sexual Development: XY DSD has a normal male chromosomal component (XY) and a female phenotype. They have abnormal gonadal development that drives phenotypic abnormalities, abnormal androgen synthesis, or lack androgen receptors. They are described according to the presence or absence of the SRY gene and the gonadal type. The most extreme example is XY DSD, SRY-positive with testes and female phenotype. These were called male pseudohermaphrodites, testicular feminization, or XY sex reversal (Fig. 18-4). They usually lack androgen receptors. Serum testosterone is present, but the genitalia are female. A mild form occurs in Miniature schnauzers with persistent Müllerian duct syndrome. They are XY males with a complete paramesonephric system, including uterine tube, uterus, and cranial portion of the vagina. They lack the anti-Müllerian hormone (AMH, previously called Müllerian inhibitory substance) or its receptor. XY DSD, SRY negative with gonadal dysgenesis and female phenotype is another category and is found in horses and other species. They have hypoplastic or undifferentiated gonads and a female phenotype.

XX Disorders of Sexual Development: The only category of XX DSD reported in animals is XX DSD, SRY negative. Most are XX DSD, SRY negative with ovotestes and a female but ambiguous phenotype. They are usually true hermaphrodites with both male and female gonads (Fig. 18-5). They are phenotypically female, with masculinization, for example, an enlarged clitoris. American cocker spaniels and some other breeds of dog have this autosomal recessive trait. In goats, it is associated with the polled gene. Confirmation of this syndrome requires genotyping because in the case of goats, the presence of mammary development in bucks is not always an indication of an XX DSD.

Anomalies with Normal Sexual Development: There are many different anomalies found in individuals with normal genotypic, gonadal, and phenotypic sex. They include failure of the normal maturation, hypoplasia, or aplasia of parts of the internal or external genitalia. Because normal development requires such intricate timing of events, including regression of some parts, the joining of tubes and tubules, migration of components from one site to another, the interaction of genes, and hormones and local factors, it is no wonder there are myriad anomalies.

Segmental aplasia of the paramesonephric duct can affect any part and little is known of its pathogenesis. A genetic basis is implicated in shorthorn cattle, in which it is linked to the recessive gene for white coat color. The simplest form is failure of the paramesonephric duct to make a proper connection with the urogenital sinus, leaving a persistent hymen, a membrane at the site where the two precursor tissues join (Fig. 18-6). A perforated hymen sometimes persists and is not clinically significant. If the hymen is complete and there is no drainage of fluid from the uterus, the upstream portion of the vagina, cervix, and uterus distend with normal secretions. In the more severe forms of segmental aplasia, one or more segments of the vagina, cervix, uterine body, and uterine horns are absent or rudimentary. Aplasia of a segment of the uterus (Fig. 18-7) occurs in cattle. Prostaglandin can be synthesized and released from the blind ending uterine horn, just as is produced by a normally connected uterine horn. In those with a local utero-ovarian pathway for luteolysis, such as the cow, the absence of a segment of the uterus could result in insufficient PGF_2α to cause regression of the corpus luteum. In the pig, where systemic transmission of PGF_2α from the endometrium to the corpus luteum is important, prostaglandins from the blind uterine horn can have a lytic effect on the corpora lutea of pregnancy in the contralateral ovary. In the dog and cat, the uterus does not play a role in the regression of the corpus luteum.

Imperfect lateral fusion of the paired paramesonephric ducts results in anomalies. Normally the two ducts unite first at the cloacal end to form the vagina. The fusion moves cranially to form the cervix and the uterine body. Malformations caused by imperfect fusion are most common in and adjacent to the cervix. They range from a dorsoventral fibrous band in the cranial vagina, failure of fusion of the caudal cervix with bifurcation of the cervical canal, to complete duplication of the cervix and body of the uterus (uterus didelphys).

Hypoplasia (and its extreme, aplasia) of a portion of the reproductive tract apart from the tubular genitalia comes in many different degrees. Gonadal hypoplasia is common, especially in males, and these are discussed in the relevant sections.

Developmental Anomalies: Agenesis, a total lack of ovarian tissue, can involve one or both ovaries. The entire reproductive tract also can be absent. In cases of bilateral agenesis, the tubular genitalia remain infantile.

Duplication of an ovary is a rare anomaly that arises by two different mechanisms: originating separately or splitting of an already developing ovary. The latter type is close to the normally located organ and may be connected to it. This anomaly is an uncommon cause of ovarian remnant syndrome, in which previously but incompletely spayed cats and dogs come into heat (estrus) again.

Hypoplasia of the ovaries occurs most commonly in cows. It occurs in Swedish Highland cattle as an autosomal recessive trait with incomplete penetrance. It is either unilateral or bilateral. The number of primordial follicles and the proportion of Graafian follicles are fewer than normal. Ovarian hypoplasia occurs with chromosomal DSD such as XXX and X_ chromosomes in mares and XXX DSD in cows. It is usually bilateral but not symmetric. The affected ovaries are small and lack follicles or surface scars from ovulation. Microscopically, cortical stroma and ova are absent or poorly developed. The tubular genitalia remain infantile after the expected time of puberty. Other causes of an infantile reproductive tract are malnutrition or other forms of debility. Ovaries in these animals, however, have numerous primordial follicles and can respond to gonadotropic hormones after removal of the debilitating factor.

Vascular hamartomas of the ovary are incidental findings in the mare, cow, and sow. They appear as a dark red mass on the surface of the ovary and consist of connective tissue and vascular channels lined by mature endothelial cells.

Cysts In and Around the Ovary: Periovarian (paraovarian) cysts are cysts that are external to the ovary. They are common findings in dogs and cats during ovariohysterectomy (see Web Table 18-1). Intraovarian cysts are the cysts within the ovary. These should be differentiated from cystic neoplasms (see next section).

Inflammation of the Ovary: Oophoritis, or inflammation of the ovary, is rare in domestic animals. Infectious bovine rhinotracheitis virus (bovine herpesvirus 1 [BoHV-1]) viremia in experimental studies can induce necrotizing oophoritis in the postestrus cow. A cloudy fibrinous fluid fills some follicles. Microscopically, the lesions in the corpus luteum range from focal necrosis and the presence of mononuclear cells to diffuse hemorrhage and necrosis. Most affected ovaries also have necrotic follicles and mononuclear cells in the stroma. Bovine viral diarrhea (BVD) virus, a vertically and horizontally transmitted virus responsible for mild-to-fatal enteric disease and reproductive failure, can localize in bovine oocytes and cumulus cells and cause chronic oophoritis. Infection of ovarian oocytes with BVD virus is one of several possible routes of transmission of the virus from cow to fetus. Bacterial oophoritis occasionally is found in cats and dogs. In cats, it must be differentiated from feline infectious peritonitis (FIP). The inflammation is around the ovary and within the uterine tube, suggesting that the causative bacteria ascended from the uterus.

Miscellaneous Diseases of the Ovary: Supernumerary follicles occur in bovine ovaries when FSH is used in doses to cause superovulation in preparation for embryo transfer. There may be more than a dozen well-developed ovarian follicles or corpora lutea.

Adhesions between infundibulum and ovary vary from thin bands to large sheets of fibrous tissue binding the walls together. The lesion is often bilateral in cows and results from ascending infection after postpartum metritis. Physical trauma from rectal palpation and manipulation of the ovary is another possible cause; infundibular adhesions are common in beef heifers. Adhesions can obstruct or cause retention of fluids and result in a cystic infundibulum.

A small amount of hemorrhage is normal at the time of ovulation in all species. The mare is an exception because the follicles are large and the cavity of the ovulated follicle fills with blood to form a large corpus hemorrhagicum. In rare cases, the hemorrhage can be extensive enough to form an ovarian hematoma or even hemoperitoneum. If the hematoma extends through the ovulation fossa, the corpus luteum develops external to the ovarian capsule. In the mare and cow, a focal area of serositis is detectable at the point of ovulation. Progression through a fibrinous to a fibrous stage is rapid, and an “ovulation tag” is formed. The manual expression of a persistent corpus luteum in the cow sometimes results in severe periovarian hemorrhage. Organization of the hematoma results in adhesions between the ovary and adjacent structures, such as infundibulum of the uterine tube, and causes infertility. Excessive hemorrhage into follicles is sometimes present in calves, and hemorrhage into cystic follicles occurs occasionally in the bitch.

Atretic follicles are those that become arrested at any stage of development and then regress. In any estrous cycle, only one or a small number of follicles is destined to mature, whereas the others undergo atresia at various stages of maturation. A similar process occurs in seasonal anestrus and in all domestic species during pregnancy, except for the mare. Follicular atresia is considered abnormal when it is a part of any disease process that interferes with the release of or the pituitary response to GnRH. Development of the follicle can be arrested at any stage, and after an undetermined amount of time, it degenerates. The ovum undergoes apoptosis first; then the granulosa cells become pyknotic, vacuolated, and desquamate. The follicle either persists as a cyst with a partial thin lining of granulosa cells or is replaced by macrophages, theca cells, and fibrous connective tissue, eventually becoming a small scar.

Neoplasms: There are three main groups of primary ovarian neoplasms in domesticated animals: germ cell, sex cord stromal, and epithelial neoplasms. Little is known of ovarian carcinogenesis. Neoplasms rarely metastasize to the ovary of domestic mammals.

Inflammation: Uterine disease is a significant cause of infertility and mortality in some cases. Foremost of these are inflammatory diseases, usually the result of contamination of the uterus with bacteria.

Most uterine infections are the result of ascending infection that arises when the cervix is open—at estrus, parturition, or the postpartum period. Infection can descend from the ovary and uterine tube or via the hematogenous route, particularly in pregnancy when the uteroplacental interface is the site for preferential localization of organisms such as Coxiella, Chlamydia, and Ureaplasma spp. It is assumed that the placenta is the target and the endometrium is secondarily affected, but the interface of the two systems is a unique environment that is suitable for many infectious agents to multiply. Resistance of the uterus to infection is influenced by physical factors, the hormonal environment, and the innate and acquired immune mechanisms as discussed previously.

Endometritis is inflammation of the endometrium, usually to seminal fluid and bacterial infection in nonpregnant animals. In cows, herpesvirus infections are also a cause. In pregnancy, organisms that cause placentitis, fetal infection, and failure of pregnancy also cause inflammation of the endometrium. Postpartum endometritis occurs after a normal pregnancy and parturition, but endometritis is especially common and more severe after an abnormal parturition or failure of the uterus to involute. Lochia, the fluid and debris that is discharged from the uterus for a short time after parturition, must be an excellent nutrient medium for bacterial growth.

Mild cases of acute endometritis are not detectible grossly. In more severe cases of acute endometritis, the mucosa is swollen and has a corrugated surface, often with adherent fibrin and necrotic debris. At microscopic examination, neutrophils are found in the endometrial stroma and glands, with a range of surface changes from desquamation of a few surface epithelial cells to severe necrosis of the entire endometrium. Mild lesions resolve completely or incompletely with residual changes of cystic glands and periglandular fibrosis. Severe acute endometritis often becomes chronic, and necrotic endometrium is replaced by granulation tissue and subsequently fibrous tissue. Release of PGF_2α in acute endometritis in large animals with 4 or 5 days of progesterone priming causes premature regression of the corpus luteum and shortening of the estrous cycle. The loss of endometrium (which produces PGF_2α) in chronic endometritis decreases the amount of PGF_2α, especially in the mare and the cow, and results in a persistent corpus luteum.

Persistent mating-induced endometritis is recognized in mares. Affected animals are unable to resolve acute endometritis that follows mating. It is normal for inflammation, presumably because of the local effects of seminal fluid, to last 24 to 36 hours in mares. Those mares with reduced uterine contractility fail to clear this inflammation and accumulate uterine and seminal fluid in the uterus and develop persistent edema. Reduced uterine contractility, which is the result of an intrinsic dysfunction or release of nitric oxide in the endometrium, is proposed as the cause. Greater susceptibility occurs with repeated pregnancies, loss of body condition, and genetics. The position of the uterus also plays a role, and normal mares have a more horizontal uterus that allows better drainage of fluid than the more drooped or vertical orientation of susceptible mares.

In the mare, endometrial biopsy is a breeding management tool because the severity of endometritis is correlated directly with the inability of the uterus to carry a fetus to term. To give a prognosis based on the features of the endometrium, the stage of cycle, number and presence of inflammatory cells, contents of the glands, and frequency and severity of periglandular fibrosis are scored (Fig. 18-16). The endometrium of individual mares is categorized as predicted high, reduced, or low likelihood of the birth of a live foal.

Metritis is inflammation of all layers of the uterine wall (Fig. 18-17). It is a more severe and advanced form of endometritis. In its acute stage, the serosa is dull, finely granular, and has petechial hemorrhages and fine adhering strands of fibrin. Microscopically, there is edema and neutrophils in the endometrium, muscle layers, and the serosa.

Pyometra (accumulation of pus in the uterine lumen) occurs as a sequel to endometritis or metritis. It is an acute or chronic infection of the uterus with dilation and accumulation of pus in the lumen (Fig. 18-18). The closure of the cervix is not always complete, and if not, exudate is discharged into the vagina. In cows, endometritis and pyometra prevent prostaglandin release and the corpus luteum is retained thus mimicking pregnancy. In the bitch and queen, pyometra follows endometritis, which requires a corpus luteum for its development (see the discussion on cystic endometrial hyperplasia later in this chapter) (see Fig. 18-18, A and B). The color and consistency of the exudates vary with the infecting bacteria. Exudate is viscid and brown with Escherichia coli infection and creamy yellow with streptococcal infection. The uterus can be greatly distended but not necessarily uniformly. Macroscopically, necrotic, ulcerated, and hemorrhagic areas are present in the endometrium, with dry, white, thickened, finely cystic areas. Microscopically, the dry white areas have hyperplasia and squamous metaplasia, a common occurrence in chronic inflammation of any mucous membrane. The cystic areas are cystic endometrial hyperplasia (Fig. 18-19). Lesions outside the genital tract secondary to pyometra include widespread extramedullary hematopoiesis and immune complex glomerulopathy and are common in the bitch.

Noninflammatory Diseases: Torsion of the uterus occurs in pregnant animals and most frequently in the cow. It occurs rarely in the pregnant bitch and queen (Fig. 18-20) but can occur when the uterus is enlarged by pyometra or mucometra (accumulation of mucus in the uterine lumen). The rotation is around the mesometrium and occurs at the level of the cervix in the cow and mare and at the junction of the uterine horn and body in the bitch and queen. Torsion results in circulatory compromise and venous infarction. The veins, which have a lower pressure and are thinner walled, are compressed and occluded before the arteries. The uterine wall and placenta become congested and edematous. The fetus dies and mummifies or if the cervix is open enough to allow the entrance of bacteria or fungi, putrefies. The uterine wall is friable and prone to rupture.

Rupture of the uterus occurs as a sequel to torsion, in severe dystocia and during treatment of uterine diseases by infusion of drugs and fluids. The torsion and dystocia-related ruptures are likely to be in the caudal part of the uterus and are often fatal because of hemorrhage or infection. The rupture that follows overvigorous infusion of medications into the uterus occurs at the lesser curvature of an infused horn, dissects beneath the serosa and into the mesometrium, and results in inflammation around the uterus (perimetritis).

Prolapse of the uterus after parturition is important in the cow, ewe, and sow. A flaccid uterus and excessive straining are predisposing conditions. Factors that cause uterine inertia, such as prolonged dystocia, hypocalcemia, and ingestion of estrogenic plants, usually contribute to prolapse of the uterus. The anatomic structures that are prolapsed can be restricted to the previously pregnant horn, cervix, or vagina or can include all of the uterus, the bladder, and sometimes some of the small intestine. As the structures prolapse, there is vascular compromise, and congestion and edema result (Fig. 18-21). Constriction by the vaginal and vulval tissues exacerbates this by further compressing blood vessels, and as edema develops, the tissues exposed to the outside environment continue to swell, hang down further, dry, and become traumatized. This further exacerbates the swelling. Continued straining and the effects of gravity on the prolapsed tissues continue to contribute to stretching of internal structures, including ligaments and blood vessels. Hemorrhage and shock can cause death even if the uterus is manually returned to its normal anatomic position in the abdominal cavity. If the animal survives, the intervening drying, trauma, venous infarction, and infection that occur may prevent future fertility.

Retention of fetal membranes for longer than normal after parturition is common, especially in the cow. In cows, membranes are considered retained if not expelled by 24 hours postpartum and by 3 hours in the mare. In cattle, where this is studied the most, there are many processes and mechanisms thought to operate to cause the fetomaternal interface (cotyledon and endometrium) to separate. These include the following:

Trophoblasts compensate by hyperplasia. Normal separation of cotyledon from caruncle involves reduced cell proliferation and increased apoptosis of placental tissue. Parturition before there is complete “maturation” of the epithelium is believed to result in retention of placental membranes. Retention is common in cases in which cesarean section is medically necessary before the time of normal parturition because there may be insufficient time for complete maturation to occur. Infectious, nutritional, hormonal, circulatory, hereditary, and weather factors may inhibit the “maturation” process. Retained membranes can act as a nutrient medium for growth of contaminant bacteria and for the development of severe endometritis from the transient mild postparturient endometritis. Bacterial endometritis can even cause systemic disease, such as toxemia, septicemia, or disseminated intravascular coagulation (DIC).

Subinvolution of placental sites is a disease unique to the bitch. It is the longer than normal persistence of placental sites in the uterus after parturition beyond the normal 12 weeks. In the normal canine placenta, trophoblasts are found in the endometrium and around the blood vessels of the myometrium, but they rapidly degenerate in the postpartum period. Subinvolution of placental sites is identified clinically by an excessive bloody vaginal discharge that lasts for weeks or months after delivery instead of the normal 1 to 6 weeks. Grossly, subinvoluted placental sites are about twice as wide as normal sites for the same time after parturition, but their appearance is identical to normal except that fibrin adherent to the site is more prominent (Fig. 18-22). As such, multiple segmental thickenings of the walls of the uterine horns are visible from the serosal surface. The luminal surface of each site is a raised, rough, ragged, gray-to-brown plaque of hemorrhage and fibrin. Microscopically, the luminal part of the plaque consists of cell debris, hematoma, thrombus, and regenerating endometrium. In the deeper part of the site, the changes are an abundance of an eosinophilic matrix, hemorrhage, distention, and decreased density of endometrial glands. Trophoblasts appear to be more numerous in subinvolution sites than in normally involuting placental sites and are abundant at the deepest portion of the eosinophilic matrix; these cells can invade the myometrium and penetrate the full thickness of and perforate the wall of the uterus. Affected animals have a prolonged bloody discharge and can become anemic, and those dogs with coagulation disorders, such as von Willebrand’s disease, can exsanguinate. The uterus is prone to develop ascending infection, endometritis, and open pyometra.

Pseudopregnancy is an exaggerated form of a normal physiologic process. Every nonovariectomized female dog has a prolonged luteal phase of estrus, and this is called covert pseudopregnancy or physiologic pseudopregnancy. Some dogs, especially of the toy breeds, develop an exaggerated reaction. The mechanism is poorly understood, but prolactin or its receptors play a role. The presence of progesterone is necessary for the changes to occur. Overtly pseudopregnant dogs either have an increased concentration of prolactin, or they have increased sensitivity to prolactin. This can occur with a more rapid than usual decline in progesterone when dogs are spayed during diestrus. Hyperprolactinemia that occurs in response to visual stimuli of the presence of surrogate neonates results in the mammary development, lactation, maternal behavior, and other clinically apparent changes of pseudopregnancy. Uterine changes in pseudopregnancy can include the formation of structures that resemble placental sites (now called localized endometrial hyperplasia of pseudopregnancy or pseudoplacentation endometrial hyperplasia) and mucometra; obviously there are no fetuses.

Endometrial atrophy is usually the result of loss of ovarian function. It occurs (1) at anestrus, (2) with a debility such as malnutrition or cachexia, and (3) in DSD. Focal endometrial atrophy of unknown cause sometimes occurs in the mare. Atrophic endometrium is macroscopically thin. In the mare, the longitudinal folds are indistinct, and in the cow, the caruncles are flat. The uterus of the mare is the most studied microscopically because data from uterine biopsies is frequently used for the management of breeding. The endometrium of the uterus of the anestrous mare has cuboidal luminal and glandular epithelium, with short, straight glands.

Endometrial polyps are common lesions in older bitches and queens. The cause is unknown, but they usually occur with cystic endometrial hyperplasia. They are localized and often pedunculated hyperplastic nodules of endometrial stroma and glands that vary from microscopic up to several centimeters long (Fig. 18-23). They can cause obstruction of the uterine lumen and mucometra.

Endometrial hyperplasia can be localized or generalized; is an important lesion in the ewe, bitch, and queen; and is rare in the mare. Cystic follicles, granulosa cell tumors, and estrogens from plants are causes of endometrial hyperplasia in the cow. In ewes, it is caused by prolonged hyperestrogenism. Ingested estrogenic clover, such as subterranean (Trifolium subterraneum), and red (Trifolium pratense) clover is the most likely source of estrogen. In ewes, endometrial hyperplasia results in reduced fertility, dystocia, and uterine prolapse because of uterine hypotonicity. Glands of the endometrial type can develop in the cervical mucosa. Even when nonpregnant, ewes have mammary gland enlargement. Endometrial cysts develop beside and beneath the caruncles, and they are about 1 cm in diameter and are filled with clear fluid. The mycotoxin zearalenone obtained from moldy feed causes endometrial cysts in the sow. In the bitch and presumably the queen, cystic endometrial hyperplasia (CEH) is a common response of the uterus (see Fig. 18-19) that occurs in diestrus. The disease can be reproduced by estrogen priming of dogs followed by progesterone administration, but this may not be the physiologic mechanism. Bacteria are almost always present in the uterus of dogs with CEH and are probably the cause. Increased concentration of progesterone in late estrus or early diestrus and aberrant hormonal function may alter hormonal receptor expression. This may prime the uterus so that inflammation or irritation by bacteria (or other substances, such as suture material and oil) stimulates the uterus to undergo hyperplasia and the type of change seen in early pregnancy (the so-called decidual reaction).

Simple endometrial hyperplasia can be overlooked or recognizable macroscopically when the endometrium has patchy or diffuse thickening. When it is cystic, the lesion is readily recognized at surgery or at necropsy. Microscopically, the main component of endometrial hyperplasia is an increase in the size and number of glands with no change in the stroma except for edema. The glandular epithelium is progestational in appearance (i.e., the cells are columnar, hypertrophic, and hyperplastic and have a clear vacuolated cytoplasm) (see Fig. 18-18, B). As the glands become cystic with increased pressure of retained secretion the epithelium of the glands becomes flattened and simple squamous in type (compression atrophy). Mucometra and hydrometra are the accumulation of mucus and clear fluid, respectively, in the uterine lumen (Fig. 18-24, A and B). The cause is congenital or acquired obstruction of the outflow of the fluid and/or mucus that is produced by the endometrium and released when the cervix opens. However, hydrometra and mucometra can develop with excessive production in hyperestrogenism. Hydrometra and mucometra occur in pseudopregnancy, where it resolves spontaneously.

Adenomyosis is the presence of endometrium within the myometrium, and the effect generally is negligible in domestic animals, which do not menstruate. Adenomyosis is found in the cow, bitch, and queen. It is thought that endometrium is either forced into the myometrium by pressure of pregnancy or pyometra, or that the epithelium “migrates.” In primates, adenomyosis is considered part of endometriosis, which is a general term in which endometrium is found in ectopic locations. Endometriosis, in which endometrium is found on serosal surfaces, around the ovary, or in the chest, is not reported in domestic species. Macroscopic changes in adenomyosis are primarily localized thickening of the myometrium. In dramatic cases, there are cysts formed in the myometrium. Sometimes, in bitches the uterus undergoes diffuse symmetric or focal asymmetric enlargement near the cervix (Fig. 18-25). Microscopically, endometrial glands, stroma, or both are within the myometrium.

Neoplasms: Uterine neoplasms are uncommon in domestic animals. Carcinoma in the cow and leiomyoma in the bitch are the most frequently seen. Lymphoma, which affects multiples sites of the body, is a common neoplasm in the cow.

Endometrial carcinoma is well known in cattle and is found at the time of meat inspection. The cause is unknown. The early microscopic lesion is most often in the depths of the endometrial glands of the horns and less often in the body of the uterus. As it increases in size, the neoplasm thickens the uterine wall without altering the luminal epithelium. A scirrhous response, the deposition of large amounts of fibrous tissue, is a characteristic lesion and this makes the neoplasm firm and tough, and causes localized constriction bands on the serosal surface. The neoplasms can be small and annular or involve a large area of the uterine wall. Microscopically, the neoplasm is readily distinguished from normal endometrium by the increased size, pleomorphism, and disarray of the glandular epithelial cells and the accompanying scirrhous reaction. Metastases occur to the regional (iliac) lymph nodes and lungs, and they seed the serosal surfaces of the abdomen.

Lymphosarcoma in the cow in the enzootic form is caused by the bovine leukemia retrovirus and commonly affects a triad of organs, namely the heart, abomasum, and uterus, as well as the lymph nodes. In the uterus, as in other locations, the neoplastic cells can be focal, multifocal, or multifocally coalescing and up to 3 cm thick (Fig. 18-26). Affected areas are light yellow, slightly friable, and sometimes centrally necrotic and thicken or replace any or all layers of the uterine wall. An extensively involved uterus can support pregnancy, even to an advanced stage.

Uterine leiomyomas in the bitch are often multiple neoplasms and can occur in the cervix and vagina (Fig. 18-27, A and B). Estrogens likely have a role in provoking and maintaining these neoplasms. In other domestic species, however, these neoplasms are rare and tend to be solitary. They are well demarcated, unencapsulated, spheric, and vary in size. If they are small, they are confined within the wall of the vagina, cervix, or uterus or can protrude into the lumen or project to the serosal surface of the uterus or into the pelvic canal. Some luminal neoplasms, especially those in the vagina, are pedunculated, making them liable to trauma or torsion. They are usually firm, pink or white, and occasionally calcified or edematous. The color is related to the amount of fibrous tissue present along with the whorled smooth muscle cells; in the macroscopically white neoplasms, fibrous tissue is the dominant component.

Failure of Pregnancy: Maintenance of pregnancy is one of those miraculous events that defy logic, and there is probably more that is not known than is known about pregnancy and embryonic and fetal development. The fetus is allogeneic and therefore foreign to the mother. Yet it survives, even though both fetus and mother could mount an immune response to each other. Tolerance or suppression of the maternal immune system is required, but the mechanisms are incompletely understood, and there is little agreement about how this actually occurs. Mechanisms in rodents and primates are studied in detail and involve several potential processes, including:

Immunologic considerations are only part of maintenance of pregnancy. There are hormonal influences, especially maintenance of serum and uterine progesterone concentration by the corpus luteum and placenta. Stressors and systemic cytokines, such as prostaglandin, can cause luteolysis of the corpus luteum and terminate pregnancy during the time when pregnancy is dependent on the corpus luteum (all of pregnancy in cattle, goats, pigs and dogs, and up to 50 days of gestation in horses, sheep, and cats).

It is generally believed that fetuses initiate their own parturition. Disease conditions mimic normal parturition so that in conditions of fetal stress, such as maternal or fetal illness, hyperthermia, and hypoxia, the fetal pituitary secretes ACTH that results in glucocorticoid production by the fetal adrenal gland. Corticosteroids increase the synthesis of estrogens in the placenta, which causes upregulation of oxytocin receptors in the myometrium and the synthesis and release of PGF_2α from the endometrium. PGF_2α initiates myometrial contraction and causes luteolysis and a decreased progesterone production. Lysis of the corpus luteum results in relaxin secretion and a further decline in progesterone concentration. Relaxin secretion and reduced progesterone promotes placental separation from the endometrium by promoting collagenase activity. Initiation of birth by this process should result in a fresh (nonautolyzed) fetus, whereas rapid fetal death results in loss of pregnancy by other mechanisms, and the fetus, having spent additional time at body temperature, will be autolyzed.

The conceptus is the product of conception, and it is composed of the embryo, that part of the conceptus that gives rise to the adult, and the membranes. The time when embryos become fetuses is debated; some believe it is the time when the embryo develops features that allow their species and sex to be determined phenotypically and others consider it to be when the embryo begins spontaneous movement. This occurs at about 35 to 45 days of age in large animals.

Failure of pregnancy is divided into stages based on the fetus’s development and potential viability, as follows:

The exact outcome of early embryonic mortality and fetal death is unpredictable and is influenced, among other things, by the cause of the failure of pregnancy, species, stage of gestation, and number of fetuses. The main outcomes are the following:

Embryonic mortality occurs in all species, and the causes are outlined in the next section. Fetal loss with no autolysis is the norm in horses, sheep, and goats. In the bitch and queen, the lifespan of the corpus luteum is long in the nonpregnant animal and similar to pregnancy. When embryonic or fetal death occurs, the corpus luteum and products of conception may be retained until approximately the normal time of parturition. Fetal autolysis is therefore usual.

Mummification is one of the possible outcomes of fetal death. Rather than being expelled soon after death, the fetus is retained and progressively dehydrates to become a firm, dry mass, which is discolored by degraded hemoglobin to brown or black, and consists of leathery skin enclosing the other dehydrated organs (Fig. 18-28). The cause of death can be infectious or noninfectious, and organisms that promote lysis of dead tissue must be absent and the cervix must be closed to prevent the entry of putrefactive organisms. The situations in which mummification most commonly occurs are listed in Table 18-2. In twin pregnancy in the mare, the mummified fetus and the longer surviving fetus abort together before term. In parvovirus infection in the sow, mummified fetuses are retained and born at term along with live fetuses. In any species with a single fetus pregnancy, the mummified fetus can be expelled at any time or retained indefinitely.

Maceration is when the fetus becomes liquefied (Fig. 18-29). This requires bacteria in the uterus, and these could be those that caused the fetal death or they could be putrefactive organisms that entered the uterus via the cervix. In addition to disintegration of the fetus (see Fig. 18-29), the uterus has lesions also. Endometritis or pyometra is present; the type of lesion depends on whether the cervix remains open or closed. Endometritis and pyometra tend to become severe and chronic. Emphysema occurs when the bacteria are gas forming, such as clostridia. Maternal toxemia and death are likely if the bacteria produce potent exotoxins. Fetal bones resist maceration, and if the uterus eventually regains some muscular tone, the bones can cause perforation.

The general diagnostic rate published by veterinary diagnostic laboratories for determination of the cause of sporadic failure of pregnancy is about 50%. Identifying the cause of embryonic loss is very low because there are seldom embryonic or placental tissues to examine. The embryo is thought to dissolve, but the conceptus is so small that it may not be found. There are recognized infectious causes of early embryonic mortality, and the infection often occurs at or near the time of coitus or conception. Agents such as Campylobacter, Tritrichomonas, Ureaplasma, and nonspecific endometrial infections are among the common examples. It appears that chromosomal abnormalities account for the majority of noninfectious causes.

Although the overall diagnostic success rate in sporadic fetal loss (abortion) is about 50%, the success rate is greater in outbreaks. Many of the recognized causes are infectious because infections are usually easy to diagnose (Table 18-3). This has led to the general approach of determining if the loss of pregnancy is infectious or not.

Failure of Pregnancy in Domestic Animals: Each species has common and known causes and profile of lesions and conditions that result in the failure of the pregnancy. Table 18-3 lists the likely laboratory diagnostic success and the types of diseases and conditions to expect.

In most species, the known causes of failure of pregnancy are infectious diseases and therefore one of the initial diagnostic processes is to separate the causes into infectious and noninfectious. Noninfectious causes affect the fetus or placenta, or both. Knowing the normal anatomy is therefore essential, and some of the unique structures of each species are listed next. Noninfectious fetal lesions are relatively uniform across the species. Anomalies affect the fetus primarily, unless they are sufficiently severe or large to cause dystocia and subsequent maternal death. Examples are hydrocephalus, hydrops fetus, and arthrogryposis. These are found sporadically in all species.

Many of the known causes of failure of pregnancy are infectious, and some of these infectious agents affect all species (see Table 18-2). Microorganisms of the same genus produce similar lesions in different species.

Failure of Pregnancy in Horses:

Failure of Pregnancy in Ruminants (Cattle, Sheep, and Goats): The diagnostic process to determine the failure of pregnancy in ruminants is similar to that of other species. There are many similarities in the pathogenesis and morphology of the lesions of failure of pregnancy among ruminants because they all have a cotyledonary placenta. There are only several anatomically normal structures that are mistaken for lesions. These are adventitial placentation, mineralization of the membranes, and amniotic plaques.

Adventitial placentation in cattle is the formation of additional placentome (Fig. 18-37). More is seen in cows with a higher parity. It is also considered to be a hyperplastic response to inadequacy of existing placentome surface area. A reduction in the area of placentomes from the loss of caruncles can occur because of endometritis, removal of cotyledons during aggressive manipulations, removal of retained placental membranes, and chronic placentitis. Compensation for a reduced placentome area is also achieved by enlargement of the existing functional maternal caruncles. Adventitial placentation is also seen in hydroallantois and when fetuses are the result of cloning. These adventitious areas initially form near the normal placentomes but can expand to involve much of the chorionic surface.

All species have amniotic plaques (see Fig. 18-35, A). They are small raised plaques of epidermal tissue, and some may have hair growing from them. In ruminants, they are up to 2 cm in diameter and are only on the amnion, thus on the same side as the fetus. In particular, ruminants normally have mineralization of the placenta, which appears as a white lacy change, especially to the chorion.

Because the placentation of ruminants is cotyledonary, there is a large potential space between the placentomes in which exudates and agents can accumulate. Chronic placentitis involving the pericotyledonary areas and the intercotyledonary portions of the chorion is common. The lesions are stereotyped and include the following:

Most agents cause a similar change and the etiologic diagnosis depends on microbiologic examination. The list of possible infectious agents is long, although there are species of bacteria and fungi that are more prevalent in some geographic locations and in some ruminant species (see next).

Amorphous globosus is a rare and incidental finding, especially in bovine placentas. It is a type of acardiac monster and is a severely anomalous second fetus. Macroscopically, it is usually spheric, covered in hair, and attached to the placenta by a cord (see Fig. 18-36). Various organs can be identified within the structure, histologically.

Failure of Pregnancy in Pigs: The principles of diagnosis used in other species apply to pigs (disease of mother, fetus, or placenta; infectious and noninfectious disease); however, the approach in intensive pig production is different and more epidemiologic in nature. Strict biosecurity has eliminated many potential diseases.

For the majority of causes, there are no fetal or placental lesions and the testing for infectious agents is more microbiologic and molecular (i.e., polymerase chain reaction [PCR]) in nature.

Failure of Pregnancy in Dogs: Much less is written about failure of pregnancy in dogs than with production animals, in which the economic importance of pregnancy failure provides an incentive to identify the cause and prevent further disease. The following includes some traditional causes.

Failure of Pregnancy in Cats: The causes of failure of pregnancy of cats include many of the important general diseases of cats, and little is known of the mechanisms of action. Lesions are seldom seen or reported unless there are obvious fetal anomalies. Feline herpesvirus, feline leukemia virus (FeLV), feline panleukopenia virus, and FIP virus are all implicated, either directly or epidemiologically, in pregnancy failure. Cases are from maternal illness rather than from placental or fetal lesions. Bacteria implicated in disease are those that cause failure of pregnancy in a wide range of species, including Coxiella burnetii, Salmonella, and Mycoplasma.

Noninflammatory Disease: Anomalies are rare, except in the cow where there can be hypertrophy or hypoplasia of the whole structure, aplasia of one or more of the usual five rugae, tortuosity, and dilation or diverticulum formation of the cervical canal. Two entire cervices or a single bifurcated cervix is recognized. This can occur as the only lesion or it is part of a more extensive failure of proper fusion of the paired paramesonephric ducts and can be found with a divided vagina and two compete uteri.

Ewes exposed to estrogenic substances in subterranean and red clover develop a permanent infertility because of alteration of the cervix. Affected animals have a cervix that has fused cervical folds and uterine-like glands that produce less viscous mucus. Alteration of cervical mucus affects spermatozoal migration and results in reduced fertility.

Neoplastic disease of the cervix of domestic animals is very rare and unlike humans, in which cervical dysplasia and neoplasia linked to human papillomavirus types is well recognized.

Inflammatory Disease: Cervicitis usually occurs as a minor lesion concurrently with more severe endometritis or vaginitis. This is observed in specific infectious diseases, such as contagious equine metritis caused by Taylorella equigenitalis, and in nonspecific postparturient endometritis, metritis, cervicitis, and vaginitis. Inflammation restricted to the cervix can result from poorly performed traumatic artificial insemination. In cows with acute cervicitis, the caudal rugae are edematous and prolapse into the vagina. Inflammatory exudate covers the cervical simple cuboidal epithelium and collects in the vagina. The cervical mucosa is thin with epithelium and a small amount of stroma, and the underlying fibromuscular tissue is relatively impervious to infection; thus most cases of cervicitis resolve readily. Those infections that follow traumatic dystocia are likely to involve the muscle layer from the onset and can produce severe lesions, including paracervical abscesses, local peritonitis with granulating tracts into the connective tissue of the pelvic canal, stenosis with adhesions across the lumen of the cervix in areas denuded of epithelium, or cervical glandular cysts filled with mucus or neutrophils.

Disorders of Domestic Animals:

Disorders of Horses: Equine herpesvirus 3 (EHV-3) is the cause of equine coital exanthema. It is a typical genital herpesviral disease of the vulva, and the virus is spread venereally, results in transient vesicles and erosions of the external genitalia of both mares and stallions (see Fig. 18-48). Depigmentation of pigmented skin of the vulva occurs.

Disorders of Ruminants (Cattle, Sheep, and Goats): Granular vulvitis in cattle occurs with many different agents, and it is not a specific diagnosis. It simply indicates a local immune reaction to antigen. It can begin as an acute vulvitis or as a subclinical disease. Ureaplasma diversum is a classic cause of granular vulvitis. In the acute stage, there is a purulent vulvar discharge and a hyperemic vulvar mucosa with 2-mm raised granules (see Fig. 18-45). The disease can become chronic, and lesions resolve within 3 months. In about 10% of infected cows, discrete, raised, white nodules of follicular lymphoid hyperplasia, 2 to 5 mm in diameter, occur in rows or clusters on the dorsolateral wall of the vulva. Infection is usually self-limiting, but herds can have a persistent infection. The prepuce of bulls and their semen can remain infected and spread the infection during mating or artificial insemination. Reduced fertility with return to service or abortion occurs with pathogenic strains of the organism as a sequel to infection of the embryo or placenta.

Infectious pustular vulvovaginitis of cattle is caused by BoHV-1, which is similar to the BoHV-1 that is the cause of infectious bovine rhinotracheitis (IBR). The two diseases behave as separate entities, but their occurrence can overlap in a herd or in an individual animal. Vulvovaginitis is transmitted by coitus, artificial insemination, and possibly nose-to-vulva contact. The first evidence of the disease includes hyperemia and edema of the vagina and vulva; this is followed by petechial hemorrhages and slight nodularity of the mucosal surfaces because of edema within epithelial cells. A rapidly coalescing multifocal erosion of the mucosa follows (see Fig. 18-46). Microscopically, changes are detected in the epithelium, the lamina propria, and the lymphoid nodules. The epithelium develops eosinophilic intranuclear inclusions and undergoes ballooning degeneration or apoptosis, followed by desquamation, but usually without discrete stages of vesicle or pustule formation. The lamina propria is hyperemic and edematous. The subepithelial lymphoid nodules become prominent and hyperplastic. Resolution of the disease is rapid and by 7 and 10 days, the lesions are a slightly thickened epithelium and hyperplastic lymphoid nodules. Lesions are similar on the penis of affected bulls. An identical disease occurs in goats and rarely in sheep. Caprine herpesvirus 1 causes lesions in goats similar to those of bovine vulvovaginitis (see Fig. 18-47).

Disorders of Pigs: Toxicosis of pigs by the mycotoxin zearalenone found in Fusarium sp.–infected grain and corn is a cause of vaginal and vulval hypertrophy, particularly in prepubertal gilts (see Fig. 18-49). The toxin is a nonsteroidal estrogen that binds to the estrogen receptor. The vaginal and vulval lesions are stromal edema. Other effects of the mycotoxin are altered time of first estrus, both early and late, reduced numbers of live embryos, endometrial hyperplasia, and precocious mammary development.

Disorders of Dogs: In bitches, so-called nonspecific vaginitis or vulvitis is common. The lesions range from acute vaginitis to chronic granular vulvitis (see previous section).

Vaginal hyperplasia, hypertrophy, and/or prolapse of bitches are common diseases seen during the follicular stage (proestrus) of the first to third estrus periods in young animals, particularly of the brachiocephalic breeds. An increased sensitivity to estrogen is assumed, and there is excessive edema of the submucosal tissues of the vagina. The vaginal mucosa swells and interferes with coitus. Dramatic swelling can, if severe, result in vaginal tissue protruding from the vulva that becomes excoriated and ulcerated. Spontaneous regression during diestrus is the norm.

Vaginal polyps are relatively common in older bitches (see Fig. 18-50). They are often solitary, up to several centimeters in diameter, and have a thin stalk of attachment to the vaginal wall. Most are located on the ventral floor of the vagina. They are indistinguishable from leiomyomas macroscopically. Excision is usually curative.

Canine transmissible venereal tumor (CTVT) of dogs is transmitted at coitus by the transfer of intact neoplastic cells. CTVT cells have 59 chromosomes compared with the normal canine number of 78. Immunohistochemical evaluation suggests that these tumors have a histiocytic origin. Both sexes are affected. The neoplasm begins as a nodule beneath the vaginal or vestibular mucosa and when enlarged, breaks through the overlying mucosa. The lesion often begins in the dorsal wall of the vagina at the junction with the vestibule. It bulges into the lumen of the vagina and can protrude through the vulva as an ulcerated, friable mass (Fig. 18-52, A). Microscopically the neoplastic cells are large, round or oval, and uniform in size (Fig. 18-52, B) but with occasional large, bizarre nuclei. The cytoplasm is pale staining and may have peripheral vacuoles. This neoplasm can develop multifocal necrosis and spontaneously regress. Lymphocyte-mediated cytotoxicity occurs in some and results in regression of tumors. This neoplasm is particularly sensitive to vincristine. In countries with stray dogs and dogs in poor health, metastases to other sites, especially the skin, are relatively common.

Carcinoma of the vagina in bitches is a recognized entity. Some clearly arise from the urethra, especially when they extend from the urethral orifice. Others arise from vaginal epithelium, but little is known of their cause. They are phenotypically similar to transitional cell carcinomas. The long-term prognosis is poor, but the prevalence of metastatic disease varies and urethral obstruction often is the complication that is difficult to control.

Bitches develop single or multiple leiomyomas of the vagina. These usually only occur in entire bitches, so a hormonal link is proposed. Ovariohysterectomy may be curative, further supporting a hormonal dependence. The common differential diagnosis of leiomyoma is vaginal polyps (see previous discussion). These have a similar macroscopic appearance, and histologic examination is usually required to differentiate them because each is a well-circumscribed nodule up to several centimeters in diameter arising from the vaginal wall (see Fig. 18-50).

Streptococcal Mastitis: Streptococcus agalactiae was the most important pathogen of the bovine mammae in the era before adequate mamma hygiene and efficient antibacterial drugs. Resistance of cows to mastitis caused by this organism is subject to great individual variation; in general, resistance decreases with age. The mamma is the only organ affected by this organism. Streptococcus agalactiae does not persist long in the environment. Once a cow is infected, however, the organism persists in the lactiferous sinus, with periodic waves of multiplication, increase in virulence, and tissue invasion. The initial response to invasion of Streptococcus agalactiae is interstitial edema and an influx of neutrophils into the interstitium and alveoli. The alveolar epithelium undergoes either brief hyperplasia or vacuolation and then desquamates. Macrophages quickly become a component of the cell population of infected alveoli, and fibrosis rapidly obliterates the lumen of these alveoli. Edema, cellular infiltration, and fibrosis are lesions found in infected and adjacent alveoli, so that pressure is increased within the lobule and within adjacent lobules. The increased pressure causes stagnation of milk flow, thereby initiating premature involution of a portion of the gland. After the acute phase, periductal fibrosis occurs and granulation tissue replaces part of the normal cuboidal to columnar epithelium of smaller ducts. Fibrous polyps can completely obstruct milk flow. Regeneration of ductal epithelium can occur after the granulation tissue has matured and contracted. The lactiferous ducts and sinuses, with their normally two-layered columnar epithelium, are similarly but less severely affected, often going through a phase of squamous metaplasia of the epithelium.

The macroscopic appearance depends on the stage of the disease; different stages occur in different areas. Usually more than one mamma is involved. In the acute stage, there is hyperemia of the lactiferous sinus. Milk quality is altered, and strands or clumps of debris are present in the milk, or the milk is transformed into pus. The areas of parenchymal edema and cellular infiltration are gray and turgid. Groups of alveoli, in which the secretion is retained because of obstruction of the duct by granulation tissue, resemble small abscesses. Involuting parenchyma and fibrotic parenchyma appear similar to one another and can be difficult to differentiate grossly. The lactiferous sinus becomes granular and thickened because of underlying projecting areas of granulation tissue and surrounding fibrosis.

Staphylococcal Mastitis: Staphylococcus aureus has a greater propensity than Streptococcus agalactiae to invade the interstitial tissue between alveoli, and thus can induce a more severe disease. Isolates of Staphylococcus aureus obtained from bovine mammary glands range from nonpathogenic to highly pathogenic. The severest form of staphylococcal mastitis is the gangrenous form (Fig. 18-56), usually seen shortly after parturition and involving a variable proportion of the udder. Severe acute inflammation, with classic heat, redness, swelling, and pain, progresses to coldness of the affected area, a blue-black color, and fluid exudation, indicating tissue death. Microscopically, during the first 48 hours after infection with toxigenic Staphylococcus aureus, the tissue has severe interstitial edema that increases the interalveolar stromal area. Progressive swelling, vacuolation, and focal erosion of epithelial cells occur throughout the ducts and are prominent near the junction of stratified squamous epithelium and columnar epithelium of the papillary duct. The bacteria attach to epithelial cells, cause focal damage, and later can be seen on, within, and below ductal and alveolar epithelia The cellular phase of the inflammatory response is rapid, with neutrophils initially in the subepithelial tissues of the duct system, then within the epithelium, and later in the lumen of alveoli.

The less severe form follows a course similar to that of streptococcal mastitis. Initially, damage occurs to the epithelium of the lactiferous sinus and larger lactiferous ducts. Bacteria expand rapidly along the ducts and produce acute inflammation in groups of adjacent terminal alveoli. In chronically infected quarters, macrophages are the principal cell type in the epithelial lining, in lumens, and especially in the glandular interstitium. Lymphocytes increase in number, but some investigators have reported a lack of increase in plasma cells. These observations suggest that mammary lymphocytes could become hyporesponsive to antigenic stimulation in chronically infected mammary glands. Some data indicate that mammary lymphocyte function is compromised; blastogenesis is depressed in lymphocytes recovered from infected mammary glands. Studies have documented that plasma cells are prevalent in the stroma of mammary glands with chronic Staphylococcus aureus mastitis; more cells produce IgA than IgG antibody, and IgA-containing cells increase in number as the disease progresses. The extent of regeneration is uncertain; it is unclear whether damaged alveoli redevelop secretory tissue or remaining healthy tissue undergoes compensatory hypertrophy, or whether both processes occur.

In chronic suppurative staphylococcal mastitis, abscess formation follows acute disease. Abscesses, scattered and often coalescing, vary in size from those that are microscopic to those grossly visible. Sometimes staphylococcal bacteria are surrounded by rosettes of club-shaped material (the term botryomycosis was applied to such lesions). An equally important and parallel set of events occurs in the lobules not invaded by bacteria as the obstruction of milk flow by granulation tissue and pressure from surrounding fibrosis result in involution. Multiple, small, soft cream to pink nodules, some containing pus, are separated by bands of fibrous tissue. Disease caused by less pathogenic strains of staphylococci, such as nonhemolytic coagulase-negative strains, progresses less dramatically and not necessarily with obvious abscess formation. However, the same components of granulation tissue and fibrosis are present, causing obstruction and pressure, which in turn cause atrophy of adjacent lobules.

Coliform Mastitis: Coliform mastitis occurs when bacteria from the environment contaminate the opening of the papillary duct and ascend. The most common bacteria are Escherichia coli, Enterobacter aerogenes, and Klebsiella pneumoniae. Coliform bacteria probably exert their damaging effect via endotoxin acting on the vasculature. In the acute form of the disease, the lesions are hyperemia, hemorrhage, and edema of the affected areas centered on the lactiferous ducts. The fluid in the lactiferous sinus is cloudy and blood stained and has clumps of fibrin (Fig. 18-57). Microscopically, interlobular septa are edematous and fibrin thrombi are in lymph vessels. Epithelium of ducts and alveoli is necrotic, and only low numbers of inflammatory cells are within them. Coliform bacteria are numerous within both the alveoli and the epithelium. The severity of the disease in postparturient cows is attributed to a delay in the influx of neutrophils. The cow’s response to endotoxin is influenced by the stage of the reproductive cycle. The nonlactating mammary glands are much less sensitive to the effects of endotoxin than are the lactating ones.

If the cow survives endotoxemia, the necrotic mammary tissue, which can be a large portion of a mamma, separates from the viable tissue and is sequestered or eventually sloughs (Fig. 18-58). Cows in early lactation with less severe coliform mastitis often develop chronic mastitis that has alterations of hyperplasia, disorganization, and filiform processes of the epithelial lining of the papillary duct and lactiferous sinus.

Mycoplasmal Mastitis: Mycoplasma mastitis in cows occurs as individual sporadic cases or in outbreaks. Several mycoplasmas are capable of causing bovine mastitis, but Mycoplasma bovis is the most prevalent. The disease caused by Mycoplasma bovis can affect one or all mammae; mycoplasmas inoculated into one mamma often spread to all. Hematogenous spread and contamination of the teat are therefore routes by which the gland becomes infected. Affected quarters initially are enlarged, firm, and light brown and have a nodular parenchyma. The nodules are abscesses that can be up to 10 cm in diameter. Large numbers of neutrophils are found in the lobular interstitium and alveoli in the early stages. This changes with chronicity to include lymphocytes and macrophages. Early vacuolation and degeneration of alveolar epithelium is followed by hyperplasia and then by metaplasia to a relatively undifferentiated multilayered epithelial lining. Focal erosions of ductal epithelium are replaced by granulation tissue. Aggregates of lymphocytes occur in the lobular interstitium and around ducts. Interstitial fibrosis and lobular atrophy occur in the late stages. Spread of the organism to calves and resultant otitis, arthritis, and pneumonia can occur.

Granulomatous Mastitis: Granulomatous mastitis in the cow occurs when drugs for the treatment or prevention of mastitis are introduced through the teat and are contaminated with Nocardia asteroides, Cryptococcus neoformans, atypical Mycobacterium sp. (other than Mycobacterium bovis), or Candida spp. These infectious agents can also cause spontaneous mammary disease. Nocardial mastitis is the best known of these diseases because it occurs in outbreaks. Severely affected cows develop pyrexia that may last for several weeks. Cows become lethargic and lose weight, as would be expected with systemic cytokine release. The glands are hot and swollen and may have multiple abscesses or granulomas. Small white particles may be found in the exudate. Lesions in the mammary glands are centered on the lactiferous ducts and sinuses because galactophoritis is the prominent finding. Because the infection is chronic and ascending, lobules are affected to a varying degree. Granulomas and pyogranulomas predominate microscopically. These are usually surrounded by fibrous tissue, and extensive involvement results in the gland being replaced by a framework of fibrous tissue surrounding pockets of inflammatory cells and central necrotic debris (Fig. 18-59). An udder affected with cryptococcal mastitis has the same yellow gelatinous material that is typical of cryptococcal lesions elsewhere.