Session #1005

Abstract

Reproductive tract disorders arise commonly in intact pet rabbits and rodents. This presentation will provide an overview of the most common diseases in rabbits, guinea pigs, and rats.

Introduction

Reproductive tract disorders are commonly reported in intact rabbits, guinea pigs, and rats. Even though elective spay or neutering is becoming more and more common in the pet population, a number of animals remain intact, with the increased potential to develop various diseases of their reproductive tract. This presentation will focus on select diseases of the reproductive tract of rabbits, guinea pigs, and rats, and deslorelin implants as an alternative to surgical neutering will be discussed.

Rabbits

Reproductive tract disorders are mostly observed in pet rabbits rather than in production rabbits; however, a large proportion of the pet rabbit population is routinely spayed, making reproductive tract disorders much less common.

Anatomy and Physiology of the Reproductive Tract¹

Females have elliptic ovaries located close to the kidneys, long oviducts, and a “duplex” uterus which means that there is no uterine body and two cervices, one per each uterine horn. The vagina is long and flaccid and located between the bladder and colon.

The urethra opens in the vaginal floor, about halfway along the vaginal length.

Does are induced ovulators with no defined estrus cycle.

The appearance of the vulva changes with sexual receptivity:

• Nonreceptive: The vulva is pale pink and dry.
• During receptivity: The vulva is swollen, moist, and red, then becomes darker until it is purple at the end of the receptive period.
• Returns to pink about 24 hours after mating

The doe is sexually receptive within hours after copulation and can conceive within hours after kindling, making her able to reproduce very quickly.¹

Males’ inguinal canal remains open lifelong, allowing for the testes to be retracted into the abdomen. This could also allow for abdominal organs to herniate posteriorly into the scrotal sacs.

The vesicular gland is located on the dorsal surface of the urethra, at the neck of the urinary bladder, and it can be inadvertently catheterized during urinary catheterization. The other accessory glands are located within the pelvic cavity.

Both males and females have anal glands and inguinal glands.

Even though rabbits can be bred year-round, they typically undergo a period of reproductive inactivity during the winter.

Epidemiology of Reproductive Disorders

A retrospective study that included 854 necropsies and 152 biopsies showed that 27.6% of rabbits had at least one lesion in the reproductive tract on postmortem exam²:

• Ovaries showed abnormalities in 3.3% of necropsies and 16.9% of biopsies.
• Uteruses showed abnormalities in 26.8% of necropsies and 99.3% of biopsies.
• Abnormalities were very rarely detected in the vagina and oviducts.

Uterine Disorders

The overall incidence of uterine disorders increases with age, reaching over 60% in does over 5 years of age.²

Uterine Adenocarcinoma

The reported prevalence of uterine lesions was about 27% out of all necropsies of intact female rabbits. About half of these lesions were neoplastic (47–58%).²

The prevalence of uterine tumors varies a lot with age, ranging from less than 3% before 3 years of age, to 20–25% around 4 or 5 years of age, to reach about 48% in rabbits over 7 years of age. The median age is around 6 years of age.^2,3

A survey conducted in 849 nonbreeding female laboratory rabbits showed that 4.2% had uterine tumors by 3 years of age and 75% had uterine tumors by the time they were 7 years old.⁴

A retrospective study including 59 rabbits with uterine disorders found that endometrial hyperplasia was the most common finding (24 rabbits), with a mean age of 4.5 years of age, while uterine adenocarcinoma was found in 18 rabbits with a mean age of 6 years of age. Both lesions were found concurrently in 11 additional rabbits.⁵ Another retrospective study including 50 rabbits with uterine disorders found uterine adenocarcinoma to be the most common finding (54% of rabbits), while endometrial hyperplasia was observed in 26% of rabbits.⁶

Uterine adenocarcinoma is the most common neoplasia of female rabbits, and its prevalence increases with age, which is related to a progressive decrease in cellularity and increase in collagen content of the endometrium. This is a slow developing tumor but induces early local invasion. Hematogenous metastasis may occur within 1 to 2 years and is present in about 46% of cases. Metastatic spread was observed in the lungs in 80% of cases; pleura, mediastinum, peritoneum, omentum, and kidneys in 30–35% of cases; and in less than 30% of cases, metastatic spread was observed in the ovaries, diaphragm, spleen, lymph nodes, GI tract, bones, skin, brain.^2,5

Havana, Tan, and Holland breeds seem to be predisposed, while the number of litters does not seem to influence the occurrence of uterine adenocarcinoma.

Clinical signs in breeding does include decreased fertility, small litter size, increased fetal retention/resorption and stillbirths, and the diagnosis is often late. In pet rabbits, owners may report “hematuria” (serosanguinous vulvar discharge). This may be an inconsistent feature: one study showed that only 17% of rabbits with a uterine disorder would present vulvar discharge.⁵ Other clinical signs can include mammary swelling or abdominal mass/distension, and at later stages, anorexia, depression, dyspnea (in cases of metastases), or pathological fractures (bone metastasis).^3,7

Diagnosis can be achieved by palpation of the enlarged uterus or uterine masses. Adenocarcinomas often involve both uterine horns. The enlarged uterus may be visible on radiographs, but abdominal ultrasound is more sensitive to detect uterine enlargement (sensitivity up to 87.5 to 100% depending on the study). Ultrasound may also allow for differentiation between potential causes of uterine enlargement.^3,7,8 Thoracic radiographs or CT are recommended to rule out pulmonary metastasis.

Treatment involves ovariohysterectomy, which is curative as long as no metastasis are present at the time of surgery. The reported median survival time is 22 months post operatively, and the prognosis is above 80% of survival after 6 months.^3,7,8 It is worth mentioning that metastasis may not be visible grossly during surgery, so regular radiographic rechecks post operatively are recommended to monitor for metastasis. When metastasis has occurred, the prognosis is guarded to poor. Chemotherapy is anecdotally mentioned, but no efficient protocol has been reported.³

Endometrial Hyperplasia

The prevalence of endometrial hyperplasia is reported to be around 41% and increases with age: it is typically below 1% before 1.5 years old, but 29% after 7 years old. In that study, simultaneous uterine adenocarcinoma was present in 15% of necropsies and 35% of biopsies.² Endometrial hyperplasia was glandular-cystic in most cases, with some cases of papillary or mixed hyperplasia.

Clinical signs can be minimal, and endometrial hyperplasia is often an incidental finding upon OHE, although some does will show serosanguinous vulvar discharge.

Inflammatory Uterine Disorders

Inflammatory disorders were found in 6.1% of necropsies and 10% of biopsies in one study, the inflammation secondary to neoplasia not being included in these numbers.² The age of the does ranges from 6 to 124 months, with the highest incidence observed in rabbits aged from 2 to 4 years.

Endometritis was the most common inflammatory disorder, making up for 77.6% of cases and being potentially suppurative, catarrhal, lymphoplasmacytic, or necro-hemorrhagic. Metritis was observed in 2% of cases, pyometra in 2% as well, some with concurrent adenocarcinoma, and placentitis was found in less than 1% of cases.

Hydrometra/Mucometra

Hydrometra and mucometra represented 8% of uterine disorders and the median age of affected does was 3 years of age. The etiology remains unclear, but it was found to be potentially associated with uterine adenocarcinoma, endometrial hyperplasia, or endometritis. Some cases, however, showed no underlying uterine disease.²

Clinical signs include mostly abdominal distension. Abdominal ultrasound is the preferred technique for diagnosis, and ovariohysterectomy is curative.

Uterine Torsion

Uterine torsion has mostly been reported in multiparous females and represents less than 2% of uterine lesions on postmortem examinations.²

Clinical signs include abdominal distension, shock, and sometimes sudden death.¹

Endometrial Venous Aneurysm

Venous aneurysms are focal areas of abnormal venous dilation with a thin vascular wall.⁹ They have been found in 5% of female rabbit necropsies in a study, the median age being 2.7 years.² They can be an incidental finding or cause clinical signs such as hemorrhage from the vulvar and/or vulvar discharge, which has been reported in 79% of cases.^1,9,10

Other Uterine Disorders

Other uterine disorders are rarer and include endometrial cysts, adenomyosis, prolapse, congenital abnormalities, and extrauterine pregnancy.

Endometrial polyps have also been noticed in 3% of cases, with a median age of 3 years. Those cases usually presented with multiple polyps.²

Ovarian Disorders

Ovarian diseases are not common overall. Most ovarian lesions are cysts, found at a median age of 4 years, and macroscopically visible in about a third of cases²:

• 68% of cysts were follicular, and about 32% were cysts of the rete ovarii.
• 76% of cases with cystic ovaries had concomitant uterine disease.
• Necrosis and dystrophic calcification of the ovaries were observed in 6% of cases.

Ovarian Tumors

Ovarian tumors represented about 32% of ovarian lesions found on postmortem exams. The median age of affected does was 7 years old for those with primary tumors (1/4 of cases) and 6 years old for those with metastatic ovarian tumors (3/4 of cases, 83% of which were from uterine adenocarcinoma).²

Clinical signs of ovarian tumors are often an incidental finding during necropsy, but they can induce hormonal disturbances or metastasize.¹

Vaginal Disorders

Vulvar Prolapse¹

Prolapse through the vulva is rare but may occur within days after kindling. A genetic predisposition is also suspected.

Clinical signs include anorexia and straining, with a protruding vulvar mass (vagina vs. uterus vs. bladder).

Treatment depends on the prolapsed organ. For the uterus or vagina, prolapse reduction followed by ovariohysterectomy should be performed. A prolapsed bladder carries a guarded to poor prognosis, and treatment with cystopexy, potentially associated with partial cystectomy, can be attempted.

Mammary Gland Disorders

Lactation can occur in does due to pseudopregnancy, which is the most common cause. It can also be a sign of a uterine disease such as adenocarcinoma or endometrial hyperplasia.¹ Pituitary adenoma secreting prolactin (prolactinoma) has been reported but appears rare.^11,12

Mastitis may occur but is rare and mostly seen in breeding females. Clinical signs include swelling, mammary secretions, abscess, hyperthermia, and pain. Treatment includes antibiotics and surgery as indicated.¹

Mammary Neoplasia^13,14

A retrospective study including 109 rabbits with 119 mammary tumors showed an average age of 5.5 years (2–14 years of age). 100% of the affected rabbits were females, and no preferred location was found for mammary tumors.

105/109 rabbits had carcinomas, 8 of which showed vascular infiltration.

12% of the lesions were benign (mostly adenomas).

Testicular Disorders

Cryptorchidism¹

Cryptorchidism is defined as the absence of one or both testes. Differential diagnosis for true cryptorchidism includes previous castration, trauma, retraction, and incomplete descendance.

Cryptorchid testes are more likely to develop tumors in other species, although this is not clearly demonstrated in rabbits. It is also suspected that a bilaterally cryptorchid male should be infertile. Cryptorchid males will most likely display the unwanted behaviors of intact males, such as humping or urine spraying.

Diagnosis can be made first by inspecting the penis and scrotum thoroughly: in cases of true cryptorchidism, the scrotal sac is absent, while if a previous castration is suspected, a scar might be present. Inguinal palpation may help in localizing the missing testicle, although ultrasound may be warranted.

Treatment of true cryptorchidism should include castration. Deslorelin implant may help with unwanted behavior; however, its effects on a cryptorchid testicle have not been studied in rabbits.

Testicular Neoplasia^1,15,16

The incidence of testicular neoplasia is reported to be around 1.9%, mostly in older males with an average age of 7.5 years.

Tumor types:

• Interstitial cell tumors (Leydig cell tumors): 71% of testicular tumors. These have been reclassified as granular cell tumors in one study.¹⁵
• Sertoli cell tumors: 16%
• Other tumors (seminomas, leiomyosarcomas, teratomas)

Clinical signs include increased size of one testicle, and possibly dysuria. One of the differential diagnoses for testicular enlargement is testicular torsion, which can occur without age predisposition and cause testicular swelling, pain, anorexia, and depression, with a testicle that is firm and painful on palpation.

Treatment involves castration, which is usually curative as metastases are rare.

Inguinal Hernia¹

Inguinal hernia has been reported mostly in older intact male rabbits, with a preference for the left side.

Clinical signs include inguinal swelling and dysuria in cases of bladder herniation, which can evolve into anuria if the urethra becomes obstructed.¹⁷ Rabbits can also be urinating outside the litter box and have perineal scalding.

Treatment includes castration and closure of the inguinal ring.

Deslorelin Implant in Rabbits¹⁸

The use of the 4.7 mg deslorelin implant has been studied in both males and females.

Males

One promising case reported the use of a deslorelin implant to control aggression, hypersexuality, and territorial marking. An initial flare up was observed for 14 days after placement, with increased testosterone concentrations, then testosterone concentrations remained too low to be measured for 7 months post implant placement and testes size decreased by 50%. During that time, no sexual behavior toward the intact female rabbit was observed.¹⁹

In a research setting, 4- to 5-month-old rabbits received the 4.7 mg implant subcutaneously. Their testosterone concentrations remained the same as controls for 3 months, and histology of the testes 90 days post implant showed that spermatogenesis was still present, making the efficacy of the implant questionable.²⁰

Females

Like males, an initial report seemed promising: 8 females were implanted and housed with an intact male, and they showed delayed pregnancy compared to the control group. The report, however, did not elaborate on the extent of that delay.¹⁸

Another study showed estrus suppression in 7 rabbits for at least 9 months after implant placement, and estrus was subsequently successfully induced with an injection of buserelin following implant removal. However, more than half of the implanted females developed endometritis or endometrial hyperplasia before 2 years of age in that study, so the implant may not be suitable for the prevention of those changes in rabbits.²¹

A recent case reported the use of a deslorelin implant in a 5-year-old spayed female who was showing behavior changes (inappropriate urination, sexual aggression). Abdominal ultrasound showed adrenal enlargement with a nodule on the cranial pole of the left adrenal gland, and serum testosterone concentrations were increased. After implantation, reduced testosterone levels were measured, clinical signs were suppressed, and adrenal gland size decreased.²²

Guinea Pigs

A couple of studies report on the prevalence of reproductive tract disorders in guinea pigs.^23,24

Ovarian Cysts

Various types of cysts have been reported in guinea pigs, with various incidences depending on the study (Table 1).^24-29 Table 2 lists the results of these studies.

Table 1. Incidence of ovarian cysts^23,24

Table 2. Ovarian cyst characterization^23,24

Clinical signs can include abdominal distension, weight loss, hunched posture, anorexia, depression, and possibly palpable abdominal mass. Small, non-secreting cysts may be asymptomatic. Decreased fertility may be observed in breeding females.^{24,25,27,29–31}

In the case of follicular cysts, signs of hyperestrogenism may be observed^25,27,30:

• Bilateral, symmetrical, non-pruritic alopecia on the flanks and/or trunk:
• One study shows that follicular cysts represent 3% of dermatologic consults.²⁹
• Other study: Alopecia was observed in 10% of serous cysts.²⁴
• Increased clitoris size
• Hyperkeratosis/hyperpigmentation of nipples
• Aggressive behavior
• Vulvar discharge/bleeding

Diagnosis is usually achieved by a combination of palpation and abdominal ultrasound. Aspiration of the cysts is typically not recommended due to the risk of cyst rupture but may relieve pressure if surgery is not an option. Recollection usually occurs within days to weeks after aspiration.

Treatment:

• Surgery (ovariohysterectomy) is the typically recommended treatment, and in the case of follicular cysts causing alopecia, hair regrowth is reported within 3 months post operatively.
• Induction of luteinization of follicular cysts: GnRH (25 µg IM q14 d—2 injections) or hCG (1000 USP IM q 7–10 d—2 injections) or leuprolide acetate (100–300 UI/kg SC/IM q 3–4 weeks)

Deslorelin implants have been studied and are not recommended to treat or prevent ovarian cysts¹⁸:

• Schützehofer et al.³²: 11 nulliparous females diagnosed with ovarian cysts by ultrasonography were included. 7 were implanted and 4 were kept as controls. No variation in cyst size in any animal was observed during that study.
• Kohutova et al.³³: Deslorelin implant caused alterations of the estrous cycle in 15 females, but prolonged vaginal opening, which may predispose them to infections. Ultrasonography and histology 10 months after implant placement showed ovarian cysts, endometrial cystic hyperplasia, adenomyosis, and uterine cervix hyperplasia in the implanted females, but not in the controls.
• In males, only one study was performed in 5 guinea pigs and found no effect on testicular volume, male behavior, or testosterone concentrations. Males remained fertile and could impregnate females, and spermatogenesis was visible upon histology of testes.¹⁸

Uterine Neoplasia

Various studies report on the prevalence of uterine neoplasia in guinea pigs.^{24,25,30,34,35}

Depending on the study:

• Leiomyoma 18–46% of all uterine tumors
• Adenoma: 16–35%
• Anaplastic neoplasms: 8–23%
• Leiomyosarcoma: 8–10%
• Adenocarcinoma: About 16%

A correlation with hormone-secreting cysts is suspected as the cysts could induce increased estrogen stimulation. Tumors seem to be located either in the uterine horns, or the uterine body.

Clinical signs can include hemorrhagic vulvar discharge, but these tumors can also be asymptomatic.

Diagnosis is often made by abdominal ultrasound, cytology, or histology of removed tissues.

Treatment of choice is ovariohysterectomy.

Uterine Hyperplasia

Incidence varies according to the study and is listed in Table 3.

Table 3. Uterine hyperplasia incidence in guinea pigs^24,34,35

Endometritis/Pyometra

Uterine infections are rare, with an overall incidence of 6.4%; however, an incidence of 17.6% is reported in females of 7 to 12 months of age.²⁴

Infections are mostly occurring a few weeks after estrus or post-partum. Ovarian cysts or glandular cystic hyperplasia may predispose to infection, and one case of infection due to a uterine foreign body has been reported.³⁶

Various bacteria can cause uterine infections in guinea pigs, including B. bronchiseptica, Strep spp., Corynebacterium sp., Staph spp., Salmonella enterica, L. monocytogenes, Chlamydia caviae, E. coli.^25,30

Clinical signs include depression, hyporexia, vulvar discharge (hemorrhagic or purulent), and hunched posture.

Diagnosis can be achieved by a combination of abdominal ultrasonography and vaginal cytology.

Treatment of choice is ovariohysterectomy, but a palliative, nonsurgical option can be considered if the patient is a poor anesthesia candidate, for example, aglepristone 10 mg/kg SC on day 1, 2, and 8 associated with broad-spectrum antibiotics.

Mammary Tumors^25,30

One study showed a prevalence of 1.3%, and in that study, older males were most commonly affected.³⁷

Tumor types:

• 50–77% malignant: Tubulo-papillary carcinomas and adenocarcinomas mostly; metastases appear rare.
• 23–50% benign: Adenomas, mixed benign tumors

Diagnosis is achieved by cytology and/or histology. Because a lot of these tumors are malignant, staging should be performed prior to surgical removal.

Rats

Mammary Tumors

Rats have extensive mammary tissue, and the incidence of mammary neoplasia is reported to be between 30 and 67%.^40-43 Mammary neoplasia is more common in female rats.

Based on a study reporting on mammary masses in rats, various tumor types were found⁴⁰:

• 75% benign lesions, including non-neoplastic lesions (mammary hyperplasia, abscess, cyst). Among those, 53% were mammary fibroadenomas.
• 25% malignant tumors: 12% carcinomas, 4% fibrosarcomas, and low percentages of various non-mammary malignancies including leiomyosarcomas, spindle cell sarcomas, hemangiosarcomas, melanocytomas, mixed adnexal carcinomas, and malignant chordoma

Cytology can be frustrating for the determination of tumor type: Mammary neoplasms tend not to exfoliate well and have an inflammatory component that can be misleading. One study reports an agreement of only 22% between cytology and subsequent histology.^40,41

Pituitary tumors and mammary tumors are often found concurrently in rats, as pituitary tumors have a reported prevalence of 60 to 75%, depending on the tumor type.⁴⁰ About 40% of rats with mammary tumors were found to have other abnormalities of the reproductive tract.^40,41

Surgical removal of a benign mammary mass is curative; however, rats will frequently develop new mammary masses 1 to 8 months post operatively (median of 4.5 months). In one study, recurrence occurred in all females.^40,41

A study showed that ovariectomy at 3 months of age reduces the incidence of mammary tumors dramatically.⁴⁴ Another study showed that ovariectomy between 4.5 and 7 months of age also reduced the incidence of spontaneous mammary tumors compared to intact females.⁴⁵ It is unclear, however, whether ovariectomy at the time of mammary tumor removal has any impact on the future occurrence of mammary tumors.

The 4.7 mg deslorelin implant has been previously reported to have contraceptive effects on female rats based on vaginal smears showing no signs of the estrus cycle, but just diestrus starting 3 weeks after implant placement, and that lasted for 7 to 10 months. None of the females housed with intact males gave birth during that time.⁴⁶ In males, suppression of testes volume and gonadotropins was observed.¹⁸ Based on those results, deslorelin implants can probably be used for contraception in rats.

A study looked at the possible effect of placement of a 4.7 mg deslorelin implant after initial mammary tumor removal on the development of additional mammary tumors.⁴⁷ One of the conclusions of that study is that deslorelin implants placed within 2 months of benign mammary tumor surgical excision did not prevent subsequent mammary tumors compared to the control (nonimplanted) group, and time to new tumor development did not differ significantly between groups. Whether early implantation may help prevent mammary tumor development in rats remains unclear, and further studies are warranted.

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