Journal of Zoo and Wildlife Medicine 40(1): 147–151, 2009 Copyright 2009 by American Association of Zoo Veterinarians

PYOMETRA IN CAPTIVE LARGE FELIDS: A REVIEW OF ELEVEN CASES

Stephanie McCain, D.V.M., Ed Ramsay, D.V.M., Dipl. A.C.Z.M., Matthew C. Allender, D.V.M., M.S., Carlos Souza, D.V.M., M.S., Dipl. A.C.V.I.M. (Oncology), and Juergen Schumacher, Dr.med.vet., Dipl. A.C.Z.M.

Abstract: Eleven cases of pyometra were diagnosed in a captive exotic felid collection over 3 yr in seven African lions (Panthera leo), two tigers (P. tigris), one liger (lion-tiger crossbreed), and one leopard (P. pardus). Clinical signs included anorexia, lethargy, vulvar discharge, and vomiting. Diagnosis was based on clinical signs, complete blood cell counts, plasma biochemistry and electrolyte values, radiographs, and abdominal ultrasonography. The most com- mon findings on complete blood count and biochemistry profiles were leukocytosis (Ͼ15,000/␮L) and hyperproteinemia (Ͼ8.2 g/dL) due to increased globulins. Abdominal radiographic findings were largely nonspecific, but ultrasonography routinely showed a distended, fluid-filled uterus. Each case was treated with ovariohysterectomy and systemic antibiotic therapy. Lions were shown to be at an increased risk for developing pyometra compared with other species. Pyometra should be considered as a differential diagnosis in anorexic or lethargic intact female large felids, and ovariohyster- ectomy may be warranted in nonbreeding female lions. Key words: Pyometra, felid, ovariohysterectomy, Panthera leo, Panthera tigris, Panthera pardus.

INTRODUCTION housed 276 exotic felids, including 129 females, Pyometra is the accumulation of purulent mate- 116 of which were intact (Table 1). rial in the uterus, secondary to bacterial infection. Because animals were obtained from various This condition is well described in domestic dogs sources, prearrival information was not available on and cats and is hormonally mediated, occurring most animals. Two lions and one leopard had pro- during diestrus.3 Pyometra often occurs secondary duced offspring at some point. Eight of the cats to cystic endometrial hyperplasia (CEH), which is never received birth control. The prior contracep- thought to result from chronic progesterone expo- tive status for two lions and one tiger was un- sure. CEH is followed by secondary bacterial over- known; however, one of those lions had one known growth of normal vaginal flora that enters the uterus pregnancy prior to arriving at the facility. All cats during proestrus and estrus.3 Pyometra is seen less were housed in outdoor enclosures, with the excep- frequently in the cat than in the dog, presumably tion of the black leopard, which had access to both because the cat is an induced ovulator.6 Clinical indoor and outdoor areas. signs vary depending on whether the cervix is open All 11 animals diagnosed with pyometra in this or closed at presentation and can include vulvar dis- report were at least 5 yr old, with nine of them at charge, lethargy, fever, anorexia, vomiting, poly- least 10 yr of age (range 5–16 yr, median 12 yr) uria, and polydipsia. Although pyometra has been (Tables 1 and 2). A Fisher’s exact test was used to observed in large felids, clinical course, treatment, assess for univariate association between age and and prevalence have not been reported.9 This study occurrence of pyometra. Additionally, a Cochran- describes 11 cases of pyometra in a captive large Mantel-Haenszel test was used to assess association felid collection and their outcome after treatment. between age and occurrence of pyometra while controlling for species. The same statistical meth- CASE REPORTS ods were used to determine if species was a signif- Pyometra was diagnosed in seven African lions icant risk factor for developing pyometra. (Panthera leo), two tigers (P. tigris), one liger Clinical signs consisted of vulvar discharge (n ϭ (lion-tiger hybrid), and one leopard (P. pardus) 9), lethargy (n ϭ 9), anorexia or decreased appetite owned by a large cat sanctuary from July 2004 to (n ϭ 8), and vomiting (n ϭ 2). Vulvar discharge October 2007. During this period, the facility varied from thick and foul smelling to bloody and differed in color from white to tan to green to red. Duration of clinical signs prior to presentation From the Department of Small Animal Clinical Scienc- es, College of Veterinary Medicine, The University of ranged from 1 to 5 days (median: 3 day). Tennessee, 2407 River Drive, Knoxville, Tennessee Complete blood cell counts and plasma biochem- 37996, USA. Correspondence should be directed to Dr. istry and electrolyte profiles were performed on all McCain ([email protected]). animals at presentation. The most common abnor-

147 148 JOURNAL OF ZOO AND WILDLIFE MEDICINE

Table 1. Incidence of pyometra in intact large exotic female felids held at a large cat sanctuary over a 3-yr period according to age. Values in parentheses indicate the number of cats that developed pyometra over the total number of intact females housed at the sanctuary within the given age range.

Species Ͼ10 yr 5–10 yr Ͻ5 yr Overall incidence

Lion (Panthera leo) 62.5% (5/8) 20.0% (2/10) 0% (0/6) 29.2% (7/24) Tiger (P. tigris) 15.4% (2/13) 0% (0/41) 0% (0/19) 2.7% (2/73) Liger (lion-tiger hybrid) 100% (1/1) 0% (0/1) 0% (0/0) 50.0% (1/2) Leopard (P. pardus) 33.3% (1/3) 0% (0/0) 0% (0/0) 33.3% (1/3) Clouded leopard (Neofelis nebulosa) 0% (0/0) 0% (0/1) 0% (0/2) 0% (0/3) Cougar (Felis concolor) 0% (0/2) 0% (0/5) 0% (0/4) 0% (0/11) All species 33.3% (9/27) 3.4% (2/58) 0% (0/31) 9.5% (11/116)

mal complete blood count finding was a neutro- poor serosal detail (n ϭ 2). No abnormal radio- philic leukocytosis (n ϭ 7; range ϭ 19,700–52,500/ graphic findings were detected in one lion. Only ␮L). Remarkable plasma biochemistry values in- one animal was taken for exploratory surgery based cluded hyperproteinemia (n ϭ 9; range ϭ 8.2–9.0 on radiographic findings of a tubular soft-tissue g/dL) due to increased globulins (n ϭ 9; range ϭ opacity between the colon and urinary bladder in 4.8–6.4 g/dL), hypokalemia (n ϭ 8; range ϭ 2.7– conjunction with a leukocytosis and vulvar dis- 3.3 mEq/L), hypophosphatemia (n ϭ 7; range ϭ charge. Abdominal ultrasonography was performed 2.6–3.9 mg/dL), and hypocholesterolemia (n ϭ 4; by one of several board-certified radiologists on 10 range ϭ 102–116 mg/dL). Reference intervals used animals, and findings included a distended fluid- for each species were established by the Interna- filled uterus (n ϭ 10), thickened uterine walls (n ϭ tional Species Information System (ISIS Physiolog- 3), nodules within the uterine lumen (n ϭ 1), peri- ical Data Reference Values 2002 ed., Apple Valley, toneal effusion (n ϭ 2), and hypoechoic fluid-filled Minnesota 55124, USA). Urinalysis performed on nodules within the ovaries (n ϭ 2). free-catch samples from two lions showed protein- All anesthesias were induced after premedication uria and bacteriuria. One of these samples also with midazolam (0.1–0.2 mg/kg i.m. or p.o.; Hos- showed hematuria (3ϩ) and elevated white blood pira, Inc., Lake Forest, Illinois 60045, USA). An- cells (40–50/high power field). esthesia was induced using a combination of keta- Abdominal radiographs were obtained in six an- mine hydrochloride (2–3 mg/kg i.m.; Ketaset, Fort imals and were mostly nondiagnostic. Radiographic Dodge Animal Health, Fort Dodge, Iowa 50501, findings were often nonspecific and included a tu- USA) and medetomidine (20–30 ␮g/kg i.m.; Dom- bular soft-tissue opacity dorsal to the urinary blad- itor, Pfizer Animal Health, Exton, Pennsylvania der (n ϭ 4), displaced intestinal loops (n ϭ 2), and 19341, USA) delivered via hand injection or dart.

Table 2. Life history parameters and histopathology of 11 large felids with pyometra.

Cage mates Animal ID Age (yr) (males/females) Histopathology of ovaries and uterus

Lion 1 8 1/2 NDa Lion 2 11 0/0 ND Lion 3 11 1/2 ND Lion 4 12 2/2 ND Lion 5 14 0/2 Multiple CL,b ovarian cysts, CEHc Lion 6 5 1/1 Multiple CL, CEH Lion 7 10 1/1 Multiple CL, CEH Liger 1 16 0/0 Multiple CL, follicular cyst, CEH Tiger 1 12 0/3 Follicles in multiple stages, ovarian cyst Tiger 2 13 0/0 Multiple CL Leopard 1 14 1/1 Single CL, follicles in multiple stages, CEH

a ND, not done. b CL, corpora lutea. c CEH, cystic endometrial hyperplasia. MCCAIN ET AL.—PYOMETRA IN LARGE FELIDS 149

After endotracheal intubation, anesthesia was main- covered during a second surgery. The abdomen was tained with isoflurane (IsoFlo, Abbott Laboratories, lavaged with 17 L of normal saline, the incision North Chicago, Illinois 60064, USA) in 100% ox- was repaired, and the animal recovered with no fur- ygen. Lumbosacral epidurals were performed in six ther complications. cases using morphine (0.06–0.12 mg/kg Dura- Aerobic and anaerobic cultures of uterine tissues morph, Hospira) for additional analgesia. (n ϭ 8) or peritoneal fluid (n ϭ 1, lion 4) were Exploratory laparotomies were performed in all obtained from nine individuals. The most common individuals. Abdominal effusion was present in five bacteria isolated were Escherichia coli (n ϭ 6), cats (45%), and a uterine rupture was detected in while Pseudomonas aeruginosa was isolated in two two of these five. Both of these animals had peri- cases. The single culture of peritoneal fluid was toneal effusion evident on abdominal ultrasonog- negative. This individual did not have a ruptured raphy. An enlarged, fluid-filled uterus was seen in uterus at surgery, and unfortunately, uterine tissue every animal, and routine ovariohysterectomies was not cultured. were performed. The ovarian pedicles were double Histopathology of the reproductive tract was per- or triple ligated using 0 or 1 polydioxanone suture formed in seven cases by one of several board-cer- (PDS) (Ethicon, Somerville, New Jersey 08876, tified pathologists. Findings included one or more USA), and the vessels of the broad ligament of the corpora lutea (n ϭ 6), follicular or ovarian cysts (n uterus were either cauterized or ligated. The uterine ϭ 3), ovarian follicles in multiple stages of devel- arteries were transfixated individually, and large opment but without a corpora lutea (n ϭ 1), and carmalt clamps were placed on the uterus prior to cystic endometrial hyperplasia (n ϭ 5) (Table 2). resection. The uterine body was double or triple Both animals with ultrasonographic findings of hy- ligated using 0 or 1 PDS. In six cases, the proximal poechoic nodules associated with the ovaries had end of the uterine stump was oversewn to appose follicular cysts. Pyometra was confirmed in all sev- the mucosal edges. The abdomen was copiously la- en cases examined by the presence of a mixed in- vaged with warm sterile saline (Hospira) prior to flammatory infiltrate within the uterine lumen, as closure. To close the linea, 0, 1, or 2 PDS was used well as a mixed inflammatory infiltrate, edema, and in a simple interrupted pattern; for subcutaneous congestion within the uterine lamina propria. tissue, 2-0, 1-0, 0, or 2 PDS was used in a simple Postoperatively, treatment in all cats included continuous pattern. The skin was closed using an broad-spectrum oral antimicrobials: amoxicillin (n intradermal suture pattern with 3-0, 2-0, 1, or 2 ϭ 4; 15 mg/kg b.i.d.; Amoxi-tabs, Pfizer Animal PDS. Health, Exton, Pennsylvania 19341, USA), amoxi- Intraoperatively, all animals received lactated cillin/clavulanic acid (n ϭ 2; 20 mg/kg b.i.d.; Cla- Ringer’s solution (n ϭ 1; Hospira), normal saline vamox, Pfizer Animal Health), cephalexin (n ϭ 1; (n ϭ 2; Hospira), or Normosol-R (n ϭ8; Hospira) 35 mg/kg t.i.d.; Ivax Pharmaceuticals, Miami, Flor- i.v. at a rate of 10 ml/kg/hr. Additionally, animals ida 33137 USA), enrofloxacin (n ϭ 2; 5 mg/kg were given either ampicillin (n ϭ 4; 22 mg/kg i.v.; s.i.d.; Baytril, Bayer HealthCare LLC, Animal Sandoz, Princeton, New Jersey 08540, USA) or ce- Health Division, Shawnee Mission, Kansas 66201, fazolin (n ϭ 7; 22 mg/kg i.v.; Sandoz, Broomfield, USA), or trimethoprim/sulfamethoxazole (n ϭ 1; Colorado 80020, USA) either once or every 120 30 mg/kg b.i.d.; Mutual Pharmaceutical Co., Phil- min during surgery. Duration of surgery ranged adelphia, Pennsylvania 19124, USA). One of the from 60 to 150 min. animals that grew E. coli was switched from amox- Postoperative complications occurred in two in- icillin to marbofloxacin (5 mg/kg s.i.d.; Zeniquin, dividuals. Lion 3 was euthanized during recovery Pfizer Animal Health) after antibiotic susceptibility from anesthesia because it was nonresponsive 4 hr results were obtained. Oral analgesics using melox- after extubation. This animal had the most severe icam alone (n ϭ 3; 0.2 mg/kg s.i.d.; Metacam, leukocytosis (52,500/␮L) preoperatively of any of Boehringer Ingelhelm Vetmedica, St. Joseph, Mis- the cats in this report, and peritoneal effusion was souri 64506, USA) or a combination of meloxicam found on abdominal ultrasonography. A ruptured and tramadol hydrochloride (n ϭ 7; 1 mg/kg b.i.d.; uterus and gross peritonitis were present at surgery. Caraco Pharmaceutical Laboratories, Detroit, MI Necropsy findings were consistent with severe sub- 48202) were also prescribed. acute peritonitis. A second animal (lion 5) showed The age at which pyometra occurred in the ani- lethargy, severe bruising around the incision, and a mals in this study (range 5–16 yr, median 12 yr) small piece of omentum protruding through the in- (Table 2) is similar to the occurrence in dogs and cision 3 days postoperatively. Complete dehiscence cats, in which pyometra is more common in older of the linea alba and severe peritonitis were dis- females (6–11 yr, median 9 yr), related to repetitive 150 JOURNAL OF ZOO AND WILDLIFE MEDICINE progesterone stimulation of the uterus.6 Based on a known number of zoos, and may not necessarily sample size of 116 intact females, age was signifi- reflect true ‘‘normals’’ for this collection. cantly associated (P ϭ 0.0005) with the develop- Radiographic and ultrasonographic findings were ment of pyometra when species was not taken into also similar to those described for domestic ani- account; however, when species was controlled for, mals. Radiographs were suggestive, but not conclu- age was associated with the development of pyo- sive, of pyometra in only four of six cases; how- metra only in tigers (P ϭ 0.03, sample size ϭ 73) ever, abdominal ultrasonography was diagnostic in and not lions (P ϭ 0.10, sample size ϭ 24). Species every large felid examined and appears to be the was found to be a significant risk factor (P ϭ imaging modality of choice for the detection of 0.0009, sample size ϭ 116), even after controlling pyometra in large felids. In small animals, E. coli for age (P ϭ 0.009, sample size ϭ 166), with lions is the most common pathogen isolated,3 as was ob- being at increased risk. served in the cats in this study. Uterine contents are the preferred material for culture and sensitivity, DISCUSSION although in cases of uterine rupture, peritoneal fluid may also yield bacterial growth. It appears that Clinical signs of pyometra in the 11 large felids broad-spectrum antibiotic therapy is appropriate for in this report were similar to those described for postoperative treatment in large felids. However, domestic cats and dogs with a few notable differ- one animal had to be switched to marbofloxacin; ences. Although polyuria and/or polydipsia are thus, it is recommended to perform a bacterial cul- commonly seen in the domestic dog,3 they are not ture and sensitivity of the uterine contents in all routinely reported in domestic cats and likewise suspected cases. were not observed in any of these large felids. Although medical management of pyometra has However, outdoor housing makes evaluation of uri- been reported in domestic carnivores, ovariohyster- nation a challenge; therefore, polyuria may have ectomy was the treatment of choice for all females occurred but not been appreciated. Vulvar dis- reported here. Because all of these individuals were charge, a common clinical sign of pyometra, was housed at a sanctuary and not intended for breed- observed in all but two lions. In these two animals, ing, medical management was not considered. detection of vulvar discharge may have been hin- Pyometra in the domestic dog and cat is associ- dered because the animals are housed in large out- ated with cystic endometrial hyperplasia,2,3,6 which door enclosures or due to grooming; however, no was observed in five of the seven cases where his- matted or stained hair was observed around the vul- topathology was available. A study of the repro- va on physical exam. ductive tracts of 212 female zoo felids identified 26 Leukocytosis is a common finding in both do- cases of pyometra (12.26%), 16 of which had mod- 3 mestic carnivores with pyometra and most of the erate to severe endometrial hyperplasia.9 That study large felids in this report, although some animals evaluated 23 species of felids, both large and small, ϭ (n 4) had white blood cell counts within refer- but did not list which species had pyometra or ence intervals. Normal, or even decreased, white whether the cats were clinically ill. Of those 26 blood cells are occasionally seen in domestic ani- animals, 14 had received melengesterol acetate mals with pyometra.3 In domestic dogs and cats, contraceptive implants, which have been shown to leukopenia can be seen with septicemia or seques- increase the incidence of endometrial hyperplasia tration of white blood cells into the uterine lumen.6 in zoo felids. However, non-melengesterol acetate– Hyperproteinemia and hyperglobulinemia are com- treated felids also may develop endometrial hyper- mon findings in domestic carnivores with pyome- plasia, with the incidence increasing with age.9 tra, presumably due to chronic antigenic stimula- Eight cats in the present report had no history of tion,3 and were observed in most of the large felids receiving contraception. The contraceptive history in this study. The significance of the decreased of two lions and one tiger was unknown; however, phosphorous, cholesterol, and potassium are not one of these lions had one pregnancy prior to ar- known but have not been reported to be associated riving at the facility. with pyometra in domestic carnivores. The de- Pyometra is less common in domestic cats than creased concentrations seen in the cats of the pre- dogs,6 presumably due to induced ovulation in the sent report were not profound and may be due to cat. In induced (reflex) ovulators, uterine tissue is individual variation or other systemic diseases not exposed to progesterone only after copulation or detected. In addition, the reference intervals used artificial stimulation. This reduces the incidence of are based on means and standard deviations of cats cystic endometrial hyperplasia compared with assessed by a large number of clinicians, at an un- spontaneous ovulators like the dog, in which the MCCAIN ET AL.—PYOMETRA IN LARGE FELIDS 151 uterus is exposed to progesterone in every estrous derstanding the basic reproductive biology of wild felids cycle. Early work with lions suggested that the lion by monitoring of faecal steroids. J. Reprod. Fertility was a spontaneous ovulator,11 but a more recent Suppl. 57: 71–82. study shows the majority of lions to be induced 2. Dow, C. 1962. The cystic hyperplasia-pyometra ovulators.12 Like the domestic cat,5,8 spontaneous complex in the cat. Vet. Rec. 74: 141–146. ovulation can occur with varying frequency when 3. Feldman, E. C. 2000. The cystic endometrial hyper- plasia/pyometra complex and infertility in female dogs. housed singly or with other females.1,12 The same In: Ettinger, S. J., and E. C. Feldman (eds.). 2000. Text- appears to be true for the tiger.4,13 In contrast, the book of Veterinary Internal Medicine: Diseases of the Dog leopard has been shown to ovulate in the presence and Cat, 5th ed. W. B. Saunders Co., Philadelphia, Penn- of other females but not when housed singly, sug- sylvania. Pp. 1549–1555. gesting they do not require intromission but do re- 4. Graham, L. H., A. P. Byers, D. L. Armstrong, N. M. quire stimulation for ovulation to occur.10 Loskutoff, W. F. Swanson, D. E. Wildt, and J. L. Brown. During evaluation of the ovulation status, histopa- 2006. Natural and gonadotropin-induced ovarian activity thology of the reproductive tract demonstrated at least in tigers (Panthera tigris) assessed by fecal steroid anal- one corpus luteum in six of the seven cases, indicating ysis. Gen. Comp. Endocrinol. 147: 362–370. that ovulation had taken place within a few weeks 5. Gudermuth, D. F., L. Newton, P. Daels, and P. Con- prior to presentation (Table 2). All three lions for cannon. 1997. Incidence of spontaneous ovulation in which histopathology results were available had mul- young, group-housed cats based on serum and faecal con- tiple corpus lutea. One of these lions (lion 5) was centrations of progesterone. J. Reprod. Fertility Suppl. 51: housed only with other females, which confirms the 177–184. previous findings that intromission is not required for 6. Hedlund, C. S. 2002. Surgery of the reproductive and genital systems. In: Fossum, T.W. (ed.). Small Animal Sur- ovulation in the lion. Additionally, one of the two gery, 2nd ed. Mosby, Inc., St. Louis, Missouri. Pp. 639–644. tigers and the single liger in this report were housed 7. Hildebrandt, T. B., F. Go¨ritz, W. Boardman, T. Strike, alone and also had multiple corpus lutea, further sup- G. Strauss, and K. Jewgenow. 2006. A non-surgical uter- porting the occurrence of spontaneous ovulation in at ine lavage technique in large cats intended for treatment least some large exotic felids. of uterine infection–induced infertility. Theriogenology. Pyometra may be more common in exotic felids, 66: 1783–1786. particularly lions, than previously reported and 8. Lawler, D. F., S. D. Johnston, R. L. Hegstad, D. G. should be considered in any anorexic or lethargic Keltner, and S. F. Owens. 1993. Ovulation without cervi- intact female, particularly those older than 10 yr. It cal stimulation in domestic cats. J. Reprod. Fertility Suppl. is unclear why lions were found to be at an increased 47: 57–61. risk for developing pyometra compared with other 9. Munson, L., I. A. Gardner, R. J. Mason, L. M. Chas- species, but it may be due to differences in induction sy, and U. S. Seal. 2002. Endometrial hyperplasia and of ovulation that are not fully understood. Uterine mineralization in zoo felids treated with melengestrol ac- pathology that predisposes cats to pyometra may be etate contraceptives. Vet. Pathol. 39: 419–427. subclinical in large felids, making reproductive eval- 10. Schmidt, A. M., D. L. Hess, M. J. Schmidt, R. C. uations an important part of the annual exam.7 Pyo- Smith, and C. R. Lewis. 1988. Serum concentrations of metra should not be ruled out based on normal com- oestradiol and progesterone, and sexual behaviour during the normal oestrous cycle in the leopard (Panthera par- plete blood count and abdominal radiographic find- dus). J. Reprod. Fertil. 82: 43–49. ings, because ultrasonography may be a more sen- 11. Schmidt, A. M., L. A. Nadal, M. J. Schmidt, and sitive method for diagnosis. Institutions and N. B. Beamer. 1979. Serum concentrations of oestradiol managers should consider performing preventive and progesterone during the normal oestrous cycle and ovariohysterectomies on large exotic felids, espe- early pregnancy in the lion (Panthera leo). J. Reprod. Fer- cially lions, when offspring are not desired. til. 57: 267–272. Acknowledgments: The authors thank the staff at 12. Schramm, R. D., M. B. Briggs, and J. J. Reeves. Tiger Haven, particularly Mary Lynn Haven and 1994. Spontaneous and induced ovulation in the lion Debbie Wilkins, for their dedication to the treat- (Panthera leo). Zoo Biol. 13: 301–307. ment of animals under their care. The authors also 13. Seal, U. S., E. D. Plotka, J. D. Smith, F. H. Wright, thank Dr. Agricola Odoi at the University of Ten- N. J. Reindl, R. S. Taylor, and M. F. Seal. 1985. Immu- noreactive luteinizing hormone, estradiol, progesterone, nessee, College of Veterinary Medicine, for assis- testosterone, and androstenedione levels during the breed- tance with statistical analysis. ing season and anestrus in Siberian tigers. Biol. Reprod. LITERATURE CITED 32: 361–368. 1. Brown, J. L., L. H. Graham, N. Wielebnowski, W. F. Swanson, D. E. Wildt, and J. G. Howard. 2001. Un- Received for publication 10 January 2008