Chapter 23 CYSTIC ENDOMETRIAL HYPERPLASIA/PYOMETRA COMPLEX
PATHOPHYSIOLOGY
Hormonal Influence (Progesterone)
CYSTIC ENDOMETRIAL HYPERPLASIA.
Pyometra in the bitch is a hormonally mediated diestrual disorder. The disease is caused by a bacterial infection within the uterus and results in mild to severe and life-threatening bacteremia and toxemia. The uterus may have undergone a pathologic change that predisposed it to sepsis before development of infection; this underlying condition is called cystic endometrial hyperplasia (CEH). CEH is assumed to be caused, in part, by an abnormal uterine response to chronic and repeated exposure to progesterone. However, other factors may have a role. A model of CEH has been developed by simply placing a silk suture in the uterine lumen of bitches during diestrus (Nomura, 1995). Estrogen may augment the effect of progesterone, enhancing development of CEH (Chen et al, 2000).
CEH DOES NOT ALWAYS PRECEDE PYOMETRA.
Severe, life-threatening pyometra can occur in the absence of CEH. It is extremely rare, however, for pyometra to occur in a bitch that was not under the influence of progesterone at the time that infection began. On occasion, a bitch develops pyometra during diestrus (the progesterone-dominated phase of the ovarian cycle), but the syndrome progresses slowly, presumably because the infection is mild. In a small number of bitches, by the time the disease creates clinical signs or becomes severe enough for the owner to seek veterinary care for the dog, the ovarian cycle of the bitch may have progressed into anestrus. However, even in this situation, the disease began during diestrus.
PROGESTERONE CONCENTRATIONS.
Plasma progesterone concentration in the anestrus bitch is low (basal; <0.5 ng/ml). Progesterone concentrations remain below 1.0 ng/ml during proestrus and then begin to rise at the onset of estrus, typically being greater than 2.0 ng/ml. Progesterone concentrations continue to increase throughout estrus and continues through the first several weeks of diestrus, followed by a plateau in serum concentrations and then a slow return toward basal concentrations. The return of concentrations less than 1.0 ng/ml marks the end of diestrus.
PROGESTERONE AND INFECTION.
For approximately 9 to 12 weeks in normal bitches, following ovulation in each ovarian cycle, the plasma progesterone concentration is increased and often exceeds 40 ng/ml. During this phase, progesterone promotes or supports endometrial growth and glandular secretion while suppressing myometrial activity, allowing accumulation of uterine glandular secretions. These secretions provide an excellent environment for bacterial growth. Bacterial growth is further enhanced by inhibition of the leukocyte response to infection in the progesterone-primed uterus. Thus the uterus becomes a prime target for potential hostile takeover by bacteria. Bacterial infections associated with pyometra involve the same bacteria recognized as normal vaginal vault flora. These bacteria frequently cross the cervix and are found within the uterus during proestrus and estrus. However, there must be some combination of the ovarian (progesterone) phase of the estrous cycle and factors or changes in the uterine environment that allows overgrowth of bacteria normally isolated from this area of the anatomy.
Cystic Endometrial Hyperplasia
Progesterone-induced endometrial hyperplasia usually precedes the development of pyometra in bitches older than 6 years of age. Although pyometra is well recognized and commonly seen in bitches younger than 6 years of age, that population is less likely to have endometrial hyperplasia. Regardless of age, when pathologic hyperplasia is present and progressive, it becomes cystic, the result being cystic endometrial hyperplasia. Endometrial thickening is due to an increase in the size and number of endometrial glands, which may exhibit secretory activity. The mucosal epithelial cells are typically tortuous, with hypertrophic and clear cytoplasm. The stroma becomes edematous, and an inflammatory cell infiltrate is invariably present. CEH occasionally results in accumulation of thin or viscid fluid within the lumen of the uterus. This sterile, fluid-filled uterus is commonly referred to as hydrometra or mucometra, the degree of hydration of the mucin determining its description.
Pyometra is the most common problem associated with CEH. Much less frequently, CEH can cause infertility or chronic endometritis. Confirming the diagnosis of CEH is difficult because it is not usually associated with clinical signs unless the uterine contents become infected; this is referred to as pyometra. Confirmation of uninfected CEH requires uterine biopsy. No recognized therapy is available for CEH (Harvey, 1998).
Bacteria
Bacterial contamination of the uterus appears to be a normal phenomenon in the proestrual or estrual bitch, one that is naturally cleared before overgrowth becomes a problem. The most likely bacteria resulting in pathologic uterine infection are those known to inhabit the vaginal vault (Baba et al, 1983). These bacteria have the potential to, and commonly do, ascend through the relatively dilated cervix into the uterus during proestrus and estrus (Noakes et al, 2000). Biochemical fingerprinting of Escherichia coli (E. coli) cultured from the uterus of a bitch with pyometra showed that the organisms were identical or similar to those bacteria isolated from feces of these same dogs (Wadas et al, 1996).
The presence of bacterial flora in the vaginal tract is constant. Cervical dilation is associated with proestrus and estrus, and it is assumed that bacterial contamination of the uterus occurs during these phases of the estrous cycle (Baba et al, 1983). However, uterine infection or pathology is rare, suggesting that the inevitable “contamination” is both controlled and rapidly cleared from the normal bitch. Intrauterine bacteria, therefore, cannot solely account for the pathogenesis of pyometra. Significant uterine disease or some other predisposing factor (progesterone or estrogen administration) predisposes bitches to pyometra. Part of the predisposition is the normal postovulation increase in plasma progesterone concentrations, because pyometra is seen only during or immediately following diestrus. Exogenous progesterone administration also increases the incidence of pyometra. Therefore, contributing factors to development of pyometra are CEH, bacteria, diestrus/elevation in serum progesterone concentrations, and exogenous progesterone or estrogen administration.
The bacterium usually associated with pyometra is E. coli. However, staphylococci, streptococci, Klebsiella, Pseudomonas, Proteus, Haemophilus, Pasturella, Serratia, and other bacteria have been isolated from the uteri of bitches with pyometra (Stone, 1985; Wheaton et al, 1989). These bacteria can be identified in the vaginal tracts of healthy normal bitches. The culture results from bitches with pyometra often demonstrate a pure growth of one bacterial species. However, some bitches with pyometra have two or more bacterial isolates cultured from the uterine contents (Memon and Mickelsen, 1993). Normal bitches can have vaginal bacterial flora composed of several bacterial species or a single isolate. It is uncommon for a bitch to have no growth (Bjurstrom and LindeForsberg, 1992).
E. coli is a gram-negative bacterium containing a chemically stable, biologically active lipopolysaccharide endotoxin in the cell membrane. The endotoxin is released as bacteria die and disintegrate. Clinical endotoxemia occurs when serum levels exceed ˜0.05 ng/ml. Clinical signs of endotoxemia include hypothermia, disorientation, and signs of septic shock. The minimum lethal concentration of endotoxin in serum is approximately 0.7 ng/ml. In a review of 92 bitches with pyometra, 7 had endotoxemia. Furthermore, the release of endotoxin may be enhanced and clinical signs exacerbated by antibiotic treatment, since antibiotics should increase the rate at which bacteria die (Frannson et al, 1997; Johnston et al, 2001).
Estrogen
Exogenous estrogen, regardless of the specific chemical form used, enhances the stimulatory effect of progesterone on the uterus. This appears to be the result of estrogen sensitizing progesterone receptors and enhancing the binding of progesterone (Niskanen and Thrusfield, 1998). Supraphysiologic concentrations of estrogen resulting from exogenous administration (e.g., mismate injections) during estrus or diestrus dramatically increase the risk for developing pyometra. For this reason, estrogen injections to prevent pregnancy are strongly discouraged.
TWO DISTINCT PYOMETRA SYNDROMES: THE OLDER BITCH.
The bitch that is older than 7 or 8 years of age is prone to CEH and subsequent pyometra. This appears to be an age-related phenomenon. The syndrome results from repeated exposure to progesterone during normal diestrus phases of the estrous cycle. After years of ovarian activity, the predisposition for and incidence of CEH increase. Therefore the risk for developing pyometra becomes exaggerated in the otherwise healthy older bitch.
TWO DISTINCT PYOMETRA SYNDROMES: THE YOUNGER BITCH.
A significant number of young bitches (<6 years of age) have been diagnosed as having pyometra. It is unlikely that similar pathophysiologic processes account for uterine disease in old and young dogs. Chronic recurring exposure to progesterone cannot have occurred in these younger animals. However, a strong correlation exists between the incidence of pyometra in young dogs and estrogen administration by veterinarians attempting to prevent pregnancy (Bowen et al, 1985; Wheaton et al, 1989). Estrogen administration for accidental breedings is not recommended. If the misbred bitch is not valuable as a brood bitch, she should undergo ovariohysterectomy (be spayed). If she is of value, carrying the unwanted pregnancy to term or inducing an abortion (see Chapter 22) is preferable to estrogen therapy.
SIGNALMENT AND HISTORY
Traditional Description Versus Clinical Experience
Traditionally, pyometra has been described as a disorder of middle-aged bitches (<6 years of age). It theoretically develops after years of repetitive progesterone stimulation of the uterus, as part of each ovarian cycle. However, with the common use of estrogens for mismating in young bitches, we have seen open-cervix and closed-cervix pyometras develop in young dogs as well. This includes bitches less than 1 year of age, having just completed their first estrus. The mean age is 2.4 years in 192 bitches with open- and closed-cervix pyometra treated by the authors with PGF2α. A diagnosis of pyometra should be considered in any bitch with consistent clinical signs that appear during or immediately following diestrus, regardless of age.
Pyometra occurs in dogs of any breed. There has been a report suggesting increased risk in rough-coated Collies, Rottweilers, Cavalier King Charles Spaniels, Golden Retrievers, Bernese Mountain Dogs, and English Cocker Spaniels compared with all other breeds, including mixed breed dogs. Breeds with a low risk for pyometra include Drevers, German Shepherds, Miniature and normal-sized Dachshunds, and Swedish Hounds (Egenvall et al, 2001).
Open-Cervix Pyometra
Owner-reported signs depend on the patency of the cervix (Table 23-1). An obvious sign seen in bitches with open-cervix pyometra is a sanguineous to mucopurulent discharge from the vagina. The discharge is usually first noticed 4 to 8 weeks after standing heat. Pyometra has been diagnosed as early as the end of standing heat and as late as 12 to 14 weeks after standing heat. Other common signs include lethargy, depression, inappetence/anorexia, polyuria, polydipsia, vomiting, and diarrhea (Wheaton et al, 1989). Open-cervix pyometra may be recognized quickly in some bitches by experienced owners. These bitches can be relatively healthy aside from the abnormal vaginal discharge. The overall health of the bitch with a pyometra depends primarily on how quickly the client recognizes the problem and seeks veterinary assistance.
TABLE 23-1 CLINICAL SIGNS COMMONLY SEEN IN BITCHES WITH PYOMETRA
| Sign | Percent of Dogs |
|---|---|
| Vaginal discharge | 85 |
| Lethargy-depression | 62 |
| Inappetence/anorexia | 42 |
| Polyuria and/or polydipsia | 28 |
| Vomiting | 15 |
| Nocturia | 5 |
| Diarrhea | 5 |
| Abdominal enlargement | 5 |
Closed-Cervix Pyometra
The bitch with closed-cervix pyometra is often quite ill at the time of diagnosis compared with dogs that have open-cervix pyometra. This is due to the lack of an easily recognized, early sign of a serious problem. Specifically, dogs with closed-cervix pyometra do not have the purulent vaginal discharge seen with open-cervix infection. Instead, owners are more likely to notice insidious signs that usually include depression, lethargy, inappetence, polydipsia and/or polyuria, and weight loss. These signs, in conjunction with the vomiting and/or diarrhea associated with progressive septicemia and toxemia, can result in progressively worsening dehydration, shock, coma, and eventually death, unless owners realize that their pet is ill and seek attention.
Occasionally, owners report the observation of a vaginal discharge that lasted 1 or 2 days and occurred before the development of more serious systemic signs of illness. Because the discharge did not persist and because the bitch may have appeared healthy, veterinary consultation may have been delayed. Again, severity of illness at the time of examination depends to a large degree on the ability of the owner to recognize a problem and then seek veterinary care. A small number of bitches with closed-cervix pyometra have signs consistent with polyarthritis, secondary to bacteremia and joint infection.
PHYSICAL EXAMINATION
Abnormalities on physical examination consistent with pyometra include depression, dehydration, fever, palpable uterine enlargement, and a sanguineous to mucopurulent discharge from the vagina if the cervix is patent (“open”). The rectal temperature may be increased or within the normal range. Fever is associated with uterine inflammation and secondary bacterial infection, as well as septicemia or toxemia. With septicemia or toxemia, shock may ensue with tachycardia, prolonged capillary refill time, weak femoral pulses, and subnormal rectal temperature.
Uterine enlargement may be obvious. The uterus, however, could be difficult to palpate, especially if it is draining much of its content or if it is enlarged but flaccid. The size and weight of the dog plus the degree of abdominal relaxation also affect the ease of palpating uterine enlargement. Abdominal radiography can be used to confirm the diagnosis (one must remember that the pregnant bitch, prior to calcification of fetal skeletons, has uterine enlargement on radiographs, which could be confused with pyometra).
Overzealous palpation should be avoided to prevent uterine rupture. A palpable uterus is always considered an abnormal finding in the nonpregnant bitch in diestrus. Even if not palpable, the organ may still be massively inflamed and infected, causing obvious clinical signs.
CLINICAL PATHOLOGY
White Blood Cell Counts
The total white blood cell count in bitches with pyometra is variable. An absolute neutrophilia (usually <25,000 cells/μl) with variable degrees of cellular immaturity (presence of a “left shift,” that is, <300 bands/μl) may be observed secondary to significant infection, inflammation, and septicemia. The infection, if severe and/or chronic, may cause a “degenerative left shift” with toxic neutrophils. Although increases in total white blood cell counts are identified in a slight majority of bitches with open-cervix pyometra (50% to 75%), normal or even decreased white blood cell counts may be documented. Some of these dogs do not exhibit evidence of the overwhelming infection seen in closed-cervix pyometra. Seventy-eight of the 163 (48%) bitches with open-cervix pyometra we have treated with PGF2α had total white blood cell counts within the normal range before initiation of any therapy. Of those managed surgically, 20 of 80 (25%) had total white blood cell counts within the normal range (Wheaton et al, 1989).
Red Blood Cell Counts
Because pyometra is a chronic inflammatory disease, it is not surprising that a mild normocytic, normochromic, nonregenerative anemia (packed cell volume, 28% to 35%) often develops. The septicemia or toxemia associated with pyometra can suppress the bone marrow; this effect is most noticeable in the shift of neutrophils toward immaturity and the nonregenerative nature of the anemia. The anemia should resolve once the pyometra is corrected.
Serum Biochemistry Profile
Hyperproteinemia (total protein, 7.5 to 10.0 g/dl) and hyperglobulinemia commonly result from dehydration and/or chronic antigenic stimulation of the immune system. The BUN may be increased if dehydration and prerenal uremia are present. Occasionally, serum alanine aminotransferase (ALT) and alkaline phosphatase activities are mild to moderately increased as a result of hepatocellular damage caused by septicemia and/or diminished hepatic circulation and cellular hypoxia in the dehydrated bitch.
Urinalysis and Urine Culture
The urine specific gravity is unpredictable in bitches with pyometra because of the many variables that can affect the results. Early in the disease process, the urine specific gravity may be greater than 1.030 simply as a reflection of dehydration and the physiologic response to conserve fluids. With secondary bacterial infection, especially E. coli, toxemia develops and interferes with the resorption of sodium and chloride in the loop of Henle. This reduces renal medullary hypertonicity, impairing the ability of the renal collecting tubules to resorb free water. Polyuria and compensatory polydipsia result.
A renal tubular insensitivity to the action of antidiuretic hormone (ADH) can result in secondary nephrogenic diabetes insipidus. This represents a sequela to reversible renal tubular damage caused by E. coli endotoxins. This development may also contribute to a loss of concentrating ability. Renal tubular immune complex injury is another proposed mechanism for polydipsia/polyuria. Although not likely, prolonged polyuria and polydipsia may cause renal medullary solute washout, further impairing the kidney’s ability to conserve water. Probably as a result of the reversible renal secondary diabetes insipidus, urine becomes progressively more dilute. Isosthenuria (urine specific gravity 1.008 to 1.015) or hyposthenuria (urine specific gravity <1.008) is well recognized in bitches with pyometra. Prerenal uremia may also be present if water consumption inadequately compensates for the polyuria.
Urinary tract infections may be suspected if pyuria, hematuria, and/or proteinuria are identified on urinalysis. However, urine obtained by a midstream collection is contaminated by the vaginal discharge. We do not recommend “blind” cystocentesis techniques on dogs with suspected or known pyometra because of the risk for puncturing an infected uterus and subsequent leakage of its contents into the abdomen. Cystocentesis using ultrasound guidance reduces the risk for penetrating the uterus. If an uncontaminated urine sample is considered important, it should be obtained only with ultrasound guidance. If ultrasonography is not available, one should not routinely culture the urine of dogs with pyometra.
Proteinuria without pyuria or hematuria may also be found with pyometra. Immune complex deposition in the glomeruli causes a mixed membranoproliferative glomerulonephropathy and leakage of plasma proteins into the glomerular filtrate. The proteinuria gradually resolves with correction of the pyometra.
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