Diseases of the Uterus

Uterine Prolapse

Prolapse of the uterus is rare in the bitch but can occur just prior to or following parturition when the cervix is open. The prolapsed tissue may include one or both uterine horns. If both horns have prolapsed, the diagnosis is relatively simple. If only one horn has prolapsed, vaginoscopy may be required to differentiate the prolapsed tissue. In cases where only one horn has prolapsed, the bitch may present with abdominal discomfort and straining. The broad ligament may tear, resulting in hemorrhage from the uterine vessels. If hemorrhage occurs, the patient may present with hemoperitoneum or die quickly from exsanguination. In some cases of vaginal prolapse, the uterus can be included, along with other structures, in the prolapsed tissue [1]. Once the diagnosis of uterine prolapse is made, treatment aims are to replace it and to prevent infection. If the tissue has been severely traumatized and devitalized, the best treatment is ovariohysterectomy. Laparotomy is often required to replace the prolapsed uterus. Another option is amputation without laparotomy, taking care to avoid the bladder and urethra.

Subinvolution of Placental Sites

Subinvolution of placental sites (SIPS) is characterized by prolonged hemorrhagic vaginal discharge that persists beyond the expected emission of lochia following parturition. Serosangineous vaginal discharge is normal for the first 4 to 6 weeks postpartum during the period of endometrial reconstruction. In cases of SIPS, trophoblast cells invade deep areas of the endometrium and myometrium following placental separation during third-stage labor, resulting in frank intrauterine hemorrhage. The condition is considered to be self-limiting and there is no proven treatment. Administration of broad-spectrum systemic antibiotics does not shorten the disease course, but it is often used prophylactically to reduce the risk of concurrent endometritis. Bitches are clinically normal, afebrile, and have normal postpartum hematologic parameters. In rare cases, bitches can experience severe hemorrhage, necessitating a blood transfusion and/or ovariohysterectomy.

Uterine Infection

Endometritis is an infection and inflammatory reaction within the endometrium, whereas metritis is an infection with inflammatory changes in both the endometrium and myometrium. These conditions occur as a result of the introduction of bacteria following parturition and less commonly, following breeding. During the postpartum period, bacteria are able to ascend from the vagina to the uterus through an open cervix. Subsequently, the bitch may develop septicemia or endotoxemia. Metritis can occur in a bitch of any age and is not influenced by hormones as in the case of cystic endometrial hyperplasia (CEH)-pyometra. A bitch is more likely to develop metritis postpartum following a retained fetus, retained placenta, obstetrical manipulations, or infectious abortion, but metritis may also occur following a normal parturition. The clinical signs of metritis are those of general systemic illness, such as vomiting, anorexia, lethargy, agalactia, and hyperthermia. A malodorous vaginal discharge is usually present that is distinct from and persists longer than normal lochia. Ultrasonographic evaluation of the uterus would reveal an increase in uterine wall thickness and in luminal diameter. Fluid may or may not be present in the uterus. In the case of a retained fetus, organized areas of hyperechogenicity would be present [2]. A complete blood count would show a leukocytosis with a left shift. Radiography can also be used to detect retained fetuses and double-contrast hysterography can be used to identify a retained placenta. Histologic evaluation of the uterus following hysterectomy would show inflammatory cell infiltration into the endometrium and myometrium and an overall increase in thickness. If the bitch is not intended for breeding, or the condition is severe and a retained fetus is present, the best treatment is ovariohysterectomy. Otherwise, medical management includes the use of broad-spectrum systemic antibiotics and ecbolics to stimulate uterine evacuation. Administration of PGF2α 0.01 to 0.1 mg/kg SQ every 2 to 4 hours is continued until uterine clearance is achieved.

Cystic Endometrial Hyperplasia-Pyometra

Cystic endometrial hyperplasia (CEH)-pyometra is the most common uterine disease in older and middle-aged intact bitches and queens, with an average age of 9.36 years [3]. CEH is infrequently diagnosed in dogs younger than 4 years old and occurs slightly more often in maiden bitches. In colony-raised beagle bitches, the incidence of CEH was 15.2% [3]. However, this incidence may be an over-estimation of the occurrence in the general population as colony raised queens had a significantly higher incidence of CEH compared with feral queens [4].

CEH is a subclinical disease characterized by the proliferation and hypersecretion of endometrial glands resulting in the formation of fluid-filled cysts. Alone, CEH is not associated with any clinical signs other than infertility. CEH is generally considered to be the initiating stage that progresses into pyometra after uterine bacterial colonization occurs. Pyometra is a life-threatening illness involving the accumulation of intraluminal purulent exudate within the uterus and inflammatory cell infiltration into the layers of the endometrium and myometrium. Although CEH generally precedes pyometra, pyometra can occur without CEH.

CEH-pyometra is an endocrine disease. The condition occurs during diestrus when corpora lutea are present and progesterone concentrations are high. The average interval from the onset of proestrus to diagnosis of CEH-pyometra is 35 days (range 20-70 days).

Progesterone stimulates endometrial growth and glandular secretory activity. Progesterone also reduces myometrial contractility and maintains cervical closure. In addition, progesterone diminishes immune function by decreasing neutrophil chemotaxis and phagocytosis and increases endometrial bacterial adherence. Despite this, peripheral serum progesterone concentrations in bitches with pyometra are not higher than in normal diestrus bitches. Estrogens also have a role in the pathogenesis of CEH through the up-regulation of endometrial progesterone and estrogen receptors. However, in studies in which CEH has been experimentally induced, estrogens alone were ineffective at inducing disease. Administration of estrogens followed by progesterone or progesterone alone will induce CEH. In cases of spontaneously occurring CEH, estrogen receptor (ER) and progesterone receptor (PR) expression are increased within the surface epithelium, endometrial glands, stromal fibroblasts, and myometrium [5]. Clinically, CEH-pyometra are reported sequelae following the use of exogenous estrogens for pregnancy termination, exogenous progestins for contraception, anovulatory (cystic) follicles, and ovarian neoplasia. The use of medroxyprogesterone acetate for population control increases the prevalence of pyometra in treated bitches to 45% over a prevalence of only 5% in untreated bitches [6].

Bacteria gain access to the uterus via ascension during cervical dilation that occurs with estrus. Bacteria found in healthy uteri and the uteri of bitches with pyometra are representative of the normal microflora of the vagina and cervix. The most common bacteria isolated in cases of pyometra is Escherichia coli. Infusion of E. coli isolates obtained from bitches with pyometra into the uteri of healthy bitches resulted in the development of pyometra [7]. Certain serotypes of E. coli are more commonly associated with pyometra, indicating that these strains may possess increased virulence or arise from a concurrent urinary tract infection. The presence of the K antigen is common feature of E. coli isolates from cases of pyometra [8]. In addition, approximately 50% of E. coli isolates from cases of pyometra contain cytotoxic necrotizing factor (CNF), which reduces the integrity of the endometrial epithelium. Other less common bacteria isolated from cases of pyometra include Streptococcus sp., Enterobacter sp., Proteus sp., Klebsiella sp., and Pseudomonas sp. The mechanical irritation of bacteria within the endometrium provides a stimulus for CEH. In fact, any stimuli, from an embryo to a piece of silk thread, will stimulate local proliferation of endometrial glands and hyperplastic changes within the endometrium. In cases of mechanically induced CEH and pyometra, ER and PR expression are reduced in the surface epithelium and endometrial glands, whereas PR expression is slightly increased in the stromal fibroblasts and myometrium [5]. This may be partly due to a loss of cellular integrity caused by damage to the endometrium or due to an increased response to progesterone, which naturally causes down-regulation of the two-receptor types.

Histologic criteria and gross pathologic lesions for CEH have been categorized into five groups in an effort to classify the disease based on severity [9]. Bitches in group 1 have a slightly enlarged and rounded uterus and a histologic diagnosis of endometrial hyperplasia without endometritis. Bitches in group 2 have enlargement of the uterus less than or equal to 3 cm in diameter and a histologic diagnosis of hyperplastic endometrium with irregular cysts. Bitches in group 3 have enlargement of the uterus and uterine horns greater than or equal to 7 cm and histologic lesions consisting of a roughened endometrial surface, cysts, and endometrial ulceration. Group 4 animals are subdivided depending on the patency of the cervix. Bitches in group 4 with an open cervix (group 4A) have enlargement of the uterus and uterine horns less than or equal to 3 cm with histologic evidence of endometrial fibrous, hypertrophic myometrium and cysts. Bitches in group 4 with a closed cervix (group 4B) have enlargement of the uterus with thinning of the uterine wall and a histologic diagnosis of atrophic cysts within the endometrium and myometrium.

De Bosschere and colleagues developed a histomorphometric classification for CEH-pyometra.10 CEH can be categorized as mild or severe based on the number of cysts and the percentage of the uterus affected. CEH is recognized by an increased endometrium-to-myometrium ratio. Pyometra is distinguished from CEH by the presence of inflammatory exudate. Pyometra can be categorized as hyperplastic or atrophic. In hyperplastic pyometra, a severe inflammatory reaction exists, and more than 25% of the endometrium is occupied by luminal endometrial glands. Many large cysts are present, with an increase in endometrium-to-myometrium ratio and moderate fibroblast proliferation. With atrophic pyometra, a severe inflammatory reaction also exists, but no cysts are present, the endometrium-to-myometrium ratio is decreased, and no fibroblast proliferation occurs.

The clinical signs of pyometra include vaginal discharge (80%), fever (47%), polydipsia, polyuria, and vomiting [11]. Other symptoms include lethargy and anorexia. Uterine exudate in the form of vaginal discharge may be purulent, mucoid, or hemorrhagic. Many clinical signs of pyometra result from the effects of bacterial toxins. Neutrophilia is a common hematologic finding, ranging from 15,000 to 60,000 cells/ml. Hyperproteinemia and hyperglobulinemia may occur secondary to dehydration and antigenic stimulation. Impaired renal function (hyposthenuria and proteinuria) results from E. coli lipopolysaccharide endotoxin on distal convoluted tubules and collecting ducts causing insensitivity to antidiuretic hormone. Cytotoxic necrotizing factor positive E. coli will also cause hepatocellular damage and/or hypoxia owing to dehydration and decreased circulation resulting in increased aspartate transaminase (AST) and alanine transaminase (ALT).

Diagnosis of CEH-pyometra is made by clinical signs, abdominal palpation of an enlarged uterus, hematologic and biochemical results, and radiographs or ultrasonography revealing uteromegaly. Ultrasonography is particularly useful as it can be used to evaluate endometrial integrity, uterine wall thickness, uterine distention (Fig. 76-1) and the presence of cystic endometrial glands. In CEH without pyometra, endometrial glands are increased in size and number, appearing as 1- to 2-mm anechoic areas within the endometrium [11]. Subclinical CEH has also been identified in queens using fluoroscopy and scintigraphy, with hysterograms showing a corkscrew appearance to the uterus with irregular filling defects in the lumen [12]. It is important to note that the corkscrew appearance is normal for diestrus in both queens and bitches (Fig. 76-2). When fluid in the uterus is detected, pyometra may be differentiated from CEH with mucometra by measuring circulating prostaglandin-F metabolites (PGFM). Concentrations of PGFM >3054 pmol/l, >2388 pmol/l, or >1666 pmol/l indicate a 95%, 90%, or 80% probability of pyometra, respectively [13]. Combining PGFM results with percentage of band neutrophils present on hematologic evaluation increases the sensitivity of differentiating pyometra from mucometra to 100%. However, PGFM determination is not clinically available.

Figure 76.1. Anechoic intraluminal fluid distension of several loops of uterine horn in a bitch with a pyometra.

Figure 76.2. Corkscrew appearance of the diestrus uterine horns in a queen during a routine ovariohysterectomy surgery.

The recommended treatment for pyometra in most bitches and queens is ovariohysterectomy. Prior to surgery, the patient should be stabilized, especially if endotoxemia is present. For less severe cases of pyometra in animals intended for breeding, patients can be treated medically with PGF2α and systemic antibiotics. Prostaglandin F2α causes myometrial contractility, which expels the luminal contents. It also causes luteolysis, which decreases progesterone concentrations. Side effects of PGF2α are associated with the dose administered and include panting, salivation, anxiety, vomiting, diarrhea, urination, abdominal contractions, and ataxia within 15 minutes of administration. Side effects may last for up to 120 minutes. Therapeutic regimens using high dosages of PGF2α with infrequent treatment schedules are associated with the most severe side effects and least effective treatments. It is important to remember that the therapeutic index for PGF2α in dogs is narrow, with a lethal dose of 5.13 mg/kg for dinoprost (natural PGF2α ). Low doses (0.01-0.10 mg/kg) of PGF2α administered subcutaneously every 2 to 4 hours until complete uterine evacuation and luteolysis have occurred is a highly effective treatment. Tolerance, in the form of fewer side effects, develops after repeated treatments. In addition, most side effects of PGF2α can be avoided if it is administered intravaginally. PGF2α administered at a dose of 0.15 mg/kg in an intravaginal infusion every 12 hours for up to 12 days effectively alleviated the disease in 9 of 11 bitches treated [14]. Meyers-Wallen and coworkers reported that 40% of bitches treated for pyometra produced a litter within 1 year after treatment [15]. However, case selection for medical treatment is critical as bitches categorized in Dow’s group 3 or 4 had a 40% recurrence rate of pyometra during the first post-treatment diestrus. Of treated bitches, 77% will redevelop pyometra within 27 months post-treatment.

Mucometra

Mucometra can occur as a sequela of CEH and as a precursor to pyometra. Glandular hyperplasia causes accumulation of mucoid or serous fluid in the uterine lumen. Mucometras typically are incidental findings at ovariohysterectomy in clinically normal bitches. Diagnosis is made using ultrasonography and hematologic evaluation. Treatment for bitches not intended for breeding is ovariohysterectomy. Medical treatment for bitches intended for breeding and with mild forms of CEH is similar to that for pyometra.

Uterine Stump Pyometra

Uterine stump pyometra has a similar pathogenesis as pyometra with the exception that the patient was previously believed to have had the uterus and ovaries completely removed. In patients with a uterine stump pyometra, remnants of ovarian tissue with a variable amount of uterine tissue have been left behind following ovariohysterectomy (OHE) [16]. The clinical signs are similar to CEH-pyometra and include vulvar discharge, depression, and anorexia. Diagnosis is made by retrograde vaginography and ultrasonography that reveal single or multiple fluid-filled areas adjacent to the bladder. Treatment involves surgical resection of all remaining uterine and ovarian tissue. Simultaneous vaginopexy should be performed as a higher incidence of post-surgical urinary incontinence resulting from pelvic adhesions has been reported following this condition.

Uterine Neoplasia

Uterine neoplasia is uncommon in the bitch. Reported incidences for reproductive tract tumors range from 1% to 19% [16]. Uterine neoplasia occurs most commonly in bitches older than 10 years with no established breed predisposition. The most common benign uterine neoplasia is a leiomyoma. Uterine leiomyoma often exists without clinical signs and is an incidental finding during routine OHE. Other benign uterine tumors reported include fibroma, fibroleiomyoma, fibromyoma, fibroadenoma, adenoma, lipoma, angiolipoleiomyoma, and endometrial polyps. Malignant uterine tumors reported in the dog include adenocarcinoma, endometrial carcinoma, lymphosarcoma, hemangiosarcoma, metastatic transmissible venereal tumor, and metastatic dysgerminoma. The clinical signs of malignant uterine adenocarcinoma include a bloody or purulent vaginal discharge, dysuria, hematuria, lethargy, anorexia, and abdominal distention. Presumptive diagnosis is based on clinical signs and radiographic and ultrasonographic findings. A definitive diagnosis requires excisional biopsy with histopathologic evaluation. The treatment for all uterine neoplasms is ovariohysterectomy. The prognosis depends on the degree of local invasion and the presence of metastasis.

Uterine neoplasia is also rare in the queen. One survey of 4402 neoplasms in cats found that only 13, or 0.29%, involved the uterus [17]. In this study, the age at diagnosis ranged from 3 to 16 years (median age nine years). Among cats with uterine neoplasia, more than half are purebred. However, the over-representation of purebred cats is likely owing to an increased proportion of intact purebred queens. The most common uterine neoplasias reported in queens are leiomyomas, leiomyosarcomas, and adenocarcinomas. Concurrent mammary adenocarcinomas have been reported with cases of uterine leiomyoma and adenocarcinoma. The presenting clinical signs of queens with uterine neoplasia are variable and ranged from asymptomatic with incidental discovery at ovariohysterectomy, to infertility, weight loss, palpable abdominal mass, stranguria, hematuria, constipation, pyometra, lethargy, anorexia, and malodorous vaginal discharge. By the time of diagnosis, half of the queens with uterine adenocarcinoma had metastases and few lived longer than five months following ovariohysterectomy.