Introduction

Cystic endometrial hyperplasia (CEH) has been implicated in the development of pyometra. CEH has been considered to be an initiating stage that progresses into pyometra following bacterial colonization¹. CEH development occurs during diestrus when the corpus luteum is present and progesterone levels are high. Although CEH often precedes pyometra, CEH is not necessary for pyometra to develop.¹ Estrogen is thought to contribute to the development of pyometra by upregulating endometrial progesterone and estrogen receptors in the endometrium and by relaxing the cervix, increasing the risk of bacteria entering the uterus.^1,2

Case Report

A 6 yr old female spayed Chihuahua was presented to Texas A&M Veterinary Medical Teaching Hospital for evaluation of an intermittent vulvar discharge, lethargy, stranguria, and vomiting. The Chihuahua was reported to have had an ovariohysterectomy performed at ∼1 yr of age. The owner reported that from the time of ovariohysterectomy until the dog was 4.5 yr old, the dog had experienced no estrous behavior or vulvar discharge. In the 1.5 yr prior to presentation, the dog had experienced lethargy, vaginal bleeding, stranguria, and alopecia. The dog reportedly experienced 1–2 days duration of vaginal bleeding approximately twice monthly. The primary care veterinarian performed abdominal radiographs, and a caudal abdominal mass and enlarged liver were detected on radiographic interpretation. An abdominal ultrasound examination was performed, and a stump pyometra was suspected based on the ultrasound examination. The dog was hospitalized for 3 days with the primary care veterinarian and was administered intravenous antimicrobial therapy; the clinical signs of lethargy and stranguria resolved. Six months later, the dog developed lethargy, anorexia, and a purulent vulvar discharge. A vaginal bacterial culture was submitted, and Staphylococcus was cultured. The dog was treated with oral antimicrobial therapy, and the purulent vulvar discharge resolved for 6 mo, although vaginal bleeding continued throughout. The dog was presented again to the primary care veterinarian for vulvar bleeding, purulent vulvar discharge, lethargy, stranguria, and vomiting. Upon questioning, the owner reported that she had been applying a topical hormone replacement therapy (estradiol spray) to her own medial forearm twice daily for the duration of the dog’s clinical signs^a. On initial presentation to Texas A&M Veterinary Medical Teaching Hospital, abnormalities detected on physical examination included an enlarged vulva with a malodorous, purulent discharge. The dog had a dull hair coat, truncal alopecia, and comedones on the ventral abdomen (Figure 1). A complete blood count and serum biochemistry panel were performed. The complete blood count revealed a leukocytosis (24,800/µL, reference range = 6000–17,000/µL) with a neutrophilia (19,592 segmented neutrophils/µL, reference range = 3000–11500/µL), many döhle bodies, and moderate toxic changes. An abdominal ultrasound examination was performed, and an enlarged uterine stump with a thickened wall, an ovoid projection cranially, and echogenic luminal contents were noted. Other abnormalities of interest included diffuse abdominal lymphadenomegaly and scant peritoneal fluid. A fine-needle aspirate of the ovoid structure was obtained with ultrasound guidance. Mixed neutrophilic/histiocytic inflammation as well as squamous epithelial cells and keratinaceous/squamous debris were present on evaluation of the slides from the fine-needle aspirate. An abdominal exploratory surgery was performed. On evaluation of the reproductive tract, the uterine stump was enlarged to ∼3 cm in diameter. Adhesions between the uterine stump and the urinary bladder were present. The adhesions were removed with a combination of sharp and blunt dissection. The dissection continued along the uterine stump as far as possible caudally to the vagina, where the tissue appeared normal. The uterine stump was excised by transecting the proximal vagina. The vaginal lumen was closed with a simple interrupted suture pattern and over sewn with a Cushing pattern. No other abnormalities were detected on abdominal exploration. Special attention was given to the location of the ovarian pedicles, but no ovarian remnants were identified. The excised uterine stump was submitted for histopathologic examination, and tissue was obtained for culture. Enterococcus sp. and Escherichia coli were identified. Histopathology was performed on the excised tissue. Chronic suppurative vaginitis with mucosal hyperplasia and submucosal fibrosis was present. Furthermore, chronic fibrinosuppurative and ulcerative cervicitis and endometritis were present, with necrosis and squamous metaplasia. Intraluminal coccoid bacteria were present. Urine culture was performed, and no bacterial growth was detected. The dog recovered from surgery and was maintained on methadone (0.2 mg/kg [0.44 mg/lb] IV q 6 hr), maropitant (1 mg/kg [2.2 mg/lb] IV q 24 hr), and lactated ringer’s solution (5 mL/kg/hr [11 mL/lb/hr] IV) for 24 hr postoperatively. The dog was transitioned to tramadol (3 mg/kg [6.6 mg/lb] per os q 8–12 hr) and doxycycline (5 mg/kg [11 mg/lb] per os q 12 hr). Prior to discharge from the hospital, blood was collected to determine the dog’s estrogen level, and the sample was submitted to a reference laboratory (BET Reproduction Laboratory, Lexington, Kentucky). This sample was collected 7 days after the dog’s last interaction with the owner and 1 day postoperatively. The dog’s blood estrogen level was 56.4 pg/mL (reference range <50.0 pg/mL for a spayed bitch). The dog was discharged from the hospital, and the owner was made aware that topical estrogen sprays/creams may have contributed to the dog’s stump pyometra and dermatologic abnormalities. The owner began administering the topical medication in a different location in order to reduce possible exposure to the dog. Six weeks postsurgery, the dog’s estrogen level was tested again and was 160.3 pg/mL. At two different time points, 3 mo and 9 mo postsurgery, when the owner returned to administering estradiol spray to her forearm, blood was obtained from the dog. The estrogen levels on those two samples were 228 pg/mL and 741 pg/mL, respectively. Despite the elevated estrogen level, the dog had a normal appetite, no difficulty urinating, a normal activity level, and no vulvar enlargement or discharge.

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Discussion

To the authors’ knowledge, this is the first reported case of stump pyometra following exposure to the owner’s topical estradiol replacement medication. Typically, progesterone is implicated in the development of stump pyometra. Further, CEH often precedes pyometra and develops in response to high progesterone levels. The dog in the present report was exposed to estradiol, not progesterone, and did not have CEH on histopathologic evaluation of the uterine stump. Pyometra has been a reported sequela following the administration of estradiol as a treatment for mismating.²

Typically, stump pyometra is a sequela of endogenous hormones released from an incompletely removed ovary (ovarian remnant syndrome) in combination with retained uterine tissue and bacterial inoculation. The dog in this case report had no recognized retained ovarian tissue detected on exploratory laparotomy or abdominal ultrasound examination. The authors suspect that the dog’s accidental exposure to estradiol resulted in the stump pyometra. However, no further testing such as gonadotropin-releasing hormone stimulation test was performed, and therefore, alternative causes cannot be completely ruled out. Ideally, a vaginal cytology during estrus and gonadotropin-releasing hormone stimulation test would have been performed.³ Administration of gonadotropin-releasing hormone has been used in dogs to indirectly stimulate suspected ovarian tissue to produce estrogen which can then be measured. For the dog in this case, we suspected the estrogen was high preoperatively. This combined with fact that the dog was sick from stump pyometra resulted in our decision for surgical intervention rather than waiting to run hormonal assays. Furthermore, ultrasonographic examination is considered a sensitive modality for detection of ovarian remnants.⁴ In a majority of cases, ovarian tissue is detected in the area of the ovarian pedicles at exploratory surgery.⁴ No suspicious tissue was detected during abdominal ultrasound or exploratory laparotomy, and no tissue was removed near the ovarian pedicles. No clinical signs of estrus or proestrus have returned in the dog in the 1.5 yr following the surgery to remove the stump pyometra.

Cytologic analysis of tissue aspirated from the abdominal mass (uterine stump) prior to surgery was consistent with estrogen exposure. The presence of squamous epithelial cells was considered unusual for a spayed female and was likely a result of the dog’s exposure to estrogen. Stump pyometra is a very rare condition but should be considered in dogs with exposure to topical hormone replacement therapy. In the present case, not only did the dog have stump pyometra, but she also had dermatologic disease consistent with estrogen exposure. Alopecia secondary to human topical hormone replacement therapy has been described in dogs.^5,6 In the present case, the distribution of alopecia and the presence of comedomes is identical to the dermatologic findings described in a case series of dogs with estrogen exposure from the owner’s topical hormone replacement therapy.⁵ In that case series, many of the dogs had elevated estradiol levels as did the dog in the present report. In the present case, the owner experimented with application of the topical hormone replacement medication to different locations of her body. Estradiol levels were tested in this dog at several time points, and the site of the owner’s topical estradiol application seemed to influence the dog’s measured estradiol level. The lowest estradiol level in the dog was measured following 10 days of hospitalization without any exposure to the owner. This measured estradiol concentration was slightly over the normal reference range (56.4 pg/mL, reference range <50 pg/mL). When the owner applied the topical hormone replacement to her back, the dog’s estradiol was mildly elevated (160.3 pg/mL, reference range <50 pg/mL). During this time, the alopecic areas began to resolve. Interestingly, after the location of application was suspected to be influencing the dog’s estradiol level and the alopecia was resolving, the owner reverted to application to the medial forearms. The alopecia returned, and the dog’s estradiol level was found to be the highest measured (748.1 pg/mL, reference range <50 pg/mL). The dog in this report had an increased concentration of estradiol at every measurement. A wide variability in estradiol concentration has been reported both within and between normal dogs, and measurements often exceed the normal ranges established by the laboratory.⁷ Therefore, diagnosis of hyperestrogenism should require corroboration of clinical signs of hyperestrogenism along with elevated serum estradiol levels. Although the owner of the dog in this report reverted to application of hormone in an area that seemed to result in higher estrogen levels in the dog, our recommendation was to prevent exposure to estrogen. Clinical signs associated with hyperestrogenism can be severe including bone marrow suppression, causing both significant anemia and leukopenia, and in some cases death.^2,8 Less severe clinical signs associated with hyperestrogenism include prolonged proestrus, alopecia, comedones, and anorexia.^2,8

Conclusion

Stump pyometra is a rare condition that is mediated by hormones. Development of this condition may occur as a result of a patient’s accidental exposure to their owners’ topical hormone replacement therapy. This case is unique in that no prior published cases of stump pyometra secondary to human estradiol topical hormone replacement therapy have been described. This dog was successfully treated with surgical excision of the affected uterine stump without cessation of exposure to estradiol. When stump pyometra is diagnosed, a full work up to determine whether an ovarian remnant is present should be pursued, and consideration should be given to accidental exposure to the owner’s topical hormone replacement therapy.