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20 URETHRAL INCOMPETENCE IN DOGS CONTINUING EDUCATION

CONTINUING EDUCATION

CANINE Urethral Incompetence in Dogs: Updates in Management Julie K. Byron, DVM, MS, DACVIM The Ohio State University College of Veterinary Medicine

Urethral incompetence is the most common evaluation for other urinary tract disorders, reason for urinary incontinence in the dog. particularly urethral functional obstruction Management of these patients can start out and overflow incontinence, is warranted. as being relatively straightforward; however, many dogs need adjustments in their Medical therapy is most commonly aimed therapy as they age or develop additional at increasing urethral tone by stimulating health concerns. This article reviews the α-receptors in the smooth muscle of the urethra medical and surgical options available for with α- and/or increasing the number treatment of urethral incompetence and and sensitivity of those receptors with provides guidelines to choosing the best compounds. Estrogen also appears to have a one for each patient, as well as comments trophic effect on the periurethral tissues and on prevention for potentially at-risk dogs. vasculature and thus may reduce incontinence through improved urethral support. In MEDICAL THERAPY addition, there is ongoing investigation into other hormones in the pituitary-gonadal axis Medical therapy is considered the first and their role in urethral incompetence. line of management in dogs with acquired urethral incompetence (UI). Often it is initiated on an empirical basis, with minimal pretreatment diagnostics other than a CE TEST urinalysis and culture. In spayed To view the CE test for this article, please female dogs, this is acceptable; however, visit tvpjournal.com. in intact females and in males, further

URETHRAL INCOMPETENCE is most common in dogs who are spayed or neutered; however, the exact mechanism and relationship to estrogen and decline is unclear.

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α-Agonist Therapy poorer than in female dogs. This is possibly caused by misdiagnosis of dogs with functional urethral α-Receptors, which are part of the sympathetic obstruction and overflow incontinence. PPA has nervous system, are mediators of smooth muscle also been used safely in cats with UI, although contraction and relaxation in a variety of tissues. there are little data available regarding its efficacy. Stimulation of α1A receptors in the smooth muscle of the urethra and bladder neck leads Hypertension, or a predisposition to hypertension to increased urethral closure pressures and is caused by concurrent disease, is a major an important part of resting urethral tone. contraindication to using PPA. In otherwise healthy dogs with normal blood pressure, PPA α1-Agonists are likely the most commonly used UI rarely induced hypertension at recommended therapy in veterinary medicine. α-Agonists can be doses.3,4 However, in patients with conditions such used in dogs and cats and in both sexes. The most as chronic kidney disease, hyperadrenocorticism, serious potential is hypertension, and -losing nephropathy, it should because of the lack of specificity of the agonists be used with extreme caution and blood for the lower urinary tract and stimulation of pressure should be regularly monitored. vascular smooth muscle. Other adverse effects, such as behavioral changes and decreased A good general guideline is to perform an indirect appetite, are related to sympathetic stimulation. systolic blood pressure on any patient before treatment with PPA and repeat the evaluation Phenylpropanolamine (PPA) (Proin, after 1 to 2 weeks of therapy. Milder adverse prnpharmacal.com) is the most widely used α-agonist effects associated with PPA include restlessness, for the treatment of UI. This FDA-approved drug aggression, changes in sleeping patterns, and is commercially available in doses designed for use gastrointestinal signs. These are also usually in dogs. The dose and frequency needed for each alleviated by a reduction in dose or frequency.1,5 animal tend to vary widely and may need to be increased over time to maintain continence (Table 1). Estrogen Therapy

Clinical response to PPA administration ranges Estrogen therapy has been used to treat from 75% to 90%.1,2 Male dogs with UI can be incontinence for decades. Estrogen plays an treated with PPA; however, the response (<50%) is important role in the strength and robustness

TABLE 1 Dosages of Drugs for Management of Urethral Incompetence

DRUG CLASSIFICATION DRUG DOSAGE

α-Agonist Phenylpropanolamine 0.5–1.5 mg/kg PO q8–12h

2 mg/dog PO q24h for 14 days, then 1 mg/dog PO q24h for 14 days, then 0.5 mg/dog PO q24h, then maintenance at the lowest effective dose

Estrogen compound 1 mg/dog PO q24h for 7 days, then q 5–7 days, then adjusted for efficacy

0.02 mg/kg PO q24h for 5–7 days, then q 2–4 days, adjusting Conjugated estrogen as needed

GnRH analog Depot deslorelin acetate 5–10 mg/dog SC q 6 months*

Testosterone Testosterone cypionate 2.2 mg/kg IM monthly

*The dose listed is extrapolated from human doses; the dosing interval varies widely, with the average based on limited studies. The author recommends that the dosing interval be based on recurrence of clinical signs in the individual dog.

22 URETHRAL INCOMPETENCE IN DOGS CONTINUING EDUCATION of pelvic and periurethral tissues. It enhances worldwide to reduce complications glandular function, impacts strength, and treat a variety of conditions in women and increases the number and sensitivity until 1971; it was found to contribute to an of α-receptors in the smooth muscle of the increased risk of neoplasia and birth defects in urethra. There is strong evidence that estrogen the children of expectant mothers who took the increases the baseline resting urethral pressure drug. Since that time, DES has not been available in animal models of incontinence.6 These commercially and is only available to the veterinary compounds are usually well tolerated and are community through pharmacies. a good choice for female dogs with concurrent diseases that predispose them to hypertension DES has been used to treat UI in dogs for more or that are intolerant of α-agonist treatment. than 40 years, although there are few studies evaluating its efficacy.9 Adverse effects are similar should not be used in male dogs to those seen with other estrogens, such as because of the potential for prostatic squamous mammary and vulvar swelling and attractiveness metaplasia.7 The use of estrogens in cats with to males. As with estriol, these are usually dose- UI has not been reported and is controversial. related and subside with dose reduction. Although there has been speculation on the role of estrogens in the development of feline mammary One advantage of using DES to treat UI in dogs is neoplasia, a direct link has yet to be proven. the convenience of treating a patient on a weekly basis rather than daily (Table 1). In addition, Some practitioners avoid the use of estrogen treatment frequency can be adjusted (eg, every compounds because of the potential for 5 days rather than every 7) to accommodate irreversible myelosuppression seen in dogs the declining response to treatment in some treated with estrogen compounds for mismating patients without having to increase the or to induce estrus.8,9 While this is a potential size or medicate multiple times a day. toxicosis, the doses associated with bone marrow suppression are generally at least 10 times higher (Premarin, pfizer.com) than those recommended for management of naturally derived from the urine of pregnant UI. The need for monitoring for signs of bone mares have been used to treat a variety of marrow suppression with a complete blood postmenopausal symptoms in women. There count is controversial, and agreed-upon standard are anecdotal reports of the successful use of of care recommendations cannot be given. conjugated estrogens in spayed female dogs with However, caution should be taken when using UI (Table 1); however, no studies have been these compounds in patients with underlying published. It is likely that the efficacy and adverse myelosuppressive disease or at high doses. effect profile are similar to those of DES.

Estriol (Incurin, merck-animal-health-usa.com) -Releasing is the only commercially available FDA-approved Hormone (GnRH) Analogs estrogen for the treatment of UI in the (Table 1). Female dogs appear to have similar In the spayed female dog, the removal of the response rates to estriol and DES (89% and 87%, negative feedback effect of estrogen leads to respectively).9,10 Adverse effects with its use include increases in follicle stimulating hormone (FSH) and mammary and vulvar swelling and attractiveness (LH). It has been hypothesized to male dogs. These side effects are generally mild that the increase in these has either and resolve with appropriate dose reduction. a direct negative impact on the urethral closure pressure or results in decreased bladder function.11,12 Diethylstilbestrol (DES) is a synthetic, estrogen first synthesized in 1938. The use of depot GnRH analogs, such as depot It was widely used in the United States and deslorelin acetate (Table 1), which ultimately

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decrease LH and FSH, has been investigated Dogs that do not respond to appropriate in incontinent spayed females and was found medical therapy should be evaluated for to be 54% effective when used alone and 92% other lower urinary tract disease via imaging, effective when combined with PPA.13 Ongoing including abdominal ultrasonography and/or investigation into the use of gonadotropin contrast radiography. Cystoscopy is routinely immunization and other related therapies is performed in patients with urinary incontinence promising, although FSH and LH suppression to rule out anatomic abnormalities that may has yet to become a widespread treatment for UI. be contributing to clinical signs. Urodynamic In addition, some preparations are very costly evaluation can be performed to rule out and others are not available in . overactive bladder and confirm the diagnosis of UI. Male dogs should be evaluated for urine Testosterone Cypionate retention and functional urethral obstruction.

Testosterone cypionate has had some anecdotal For patients with UI that fail medical therapy, use in males with UI and may provide some or for which medical therapy is not an option, improvement (Table 1). It is unclear several interventional and surgical options whether this is a direct effect on the urethral exist. When evaluating the published success musculature, its support structures, or increased of these procedures, it is important to note prostatic urethral resistance. No studies have that they have primarily been evaluated in been performed to assess its efficacy in male patients that are not responding to medical dogs with UI. Adverse effects associated therapy and thus may have a more severe with testosterone supplementation include form of urethral sphincter mechanism behavior changes and prostatic . incompetence (USMI). No studies have evaluated them as first-line treatment options. FAILURE OF MEDICAL THERAPY INTERVENTIONAL PROCEDURES Frequently both an estrogen and PPA are used in the same patient for severe or refractory Urethral Bulking incontinence. Evidence supporting a synergistic increase in efficacy is controversial; however, Injectable urethral bulking agents, particularly anecdotal reports of greater improvement than bovine crosslinked collagen, have been used on a single regimen exist.14,15 to increase resting urethral pressure in dogs

A B

FIGURE 1. Urethral bulking agent. Cystoscopic view showing the placement of the needle under the urethral mucosa (A), and the final narrowed lumen after injection of bovine crosslinked collagen (B). Images courtesy of Julie K. Byron, DVM, MS, DACVIM, The Ohio State University.

24 URETHRAL INCOMPETENCE IN DOGS CONTINUING EDUCATION with UI. Although many materials have been Continence was maintained for up to 2 years investigated, the theory behind all injectable in 4 of 4 dogs.18 In a recent review, 27 of 27 bulking agents is to increase the stretch in dogs had significantly improved continence the sphincter muscle fibers, leading to an scores after placement of the sphincter, increased resting closure pressure in the urethra. with only 2 dogs having complications In addition, the implant may narrow the involving partial urethral obstruction.19 diameter of the urethral lumen, allowing the Surgical placement of an artificial urethral urethral sphincter to close more effectively. sphincter appears to have good success The material is injected submucosally into the in male dogs that fail medical therapy. proximal urethra via cystoscopy (Figure 1).

Based on two long-term reviews, postprocedure A continence in female dogs with UI was 66% to 68%; of those who are not continent, 46% to 60% achieved continence with the addition of medical therapy.16,17 The largest drawback of this procedure is the variability in duration of effect. Median duration of continence without additional medical therapy ranged from 8 months to 2 years.

SURGICAL THERAPY

Surgical management of UI is chosen for dogs intolerant of medical treatment or, most often, with progressive and refractory incontinence. Surgical therapy of urinary incontinence has traditionally focused on increasing the transmission of intra-abdominal pressure to the proximal urethra or improving the stability and pressure within the urethra.

Artificial Urethral Sphincter Placement B

A newer procedure for canine urinary incontinence is gaining in popularity and availability. The surgical placement of an artificial adjustable hydraulic urethral sphincter (Figure 2) around the urethra has been studied in female dogs and anecdotally used in males. The device allows the dog to urinate normally while maintaining continence. A small port is connected subcutaneously to the sphincter cuff and may be adjusted by injection of saline to tighten the sphincter. Anecdotally, some dogs have not needed addition of saline to the port postoperatively, FIGURE 2. The artificial urethral sphincter. Cuff, tubing, and since the placement of the sphincter itself appears attached port with Huber injection needle (A). Radiographic image (right lateral view) of the sphincter after placement around to provide enough support and occlusion of the the urethra of a dog (B). Images courtesy of Mary McLoughlin, urethra to allow continence to be maintained. DVM, MS, DACVS, The Ohio State University.

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Colposuspension Transobturator Vaginal Tape

In animals with a normally positioned bladder, The Hammock theory describes stress urinary rises in intra-abdominal pressure transmit to incontinence in women as related to weakening the proximal urethra as well as the bladder, of the structures supporting the bladder and preventing urine leakage. In animals with a urethra where they are both subject to intra- caudally positioned or “pelvic” bladder, the abdominal pressures. In humans, this is often proximal urethra is not within the abdominal managed with procedures that stabilize the cavity, and this pressure is not exerted on the mid-urethra during increases in abdominal urethra. This creates a pressure gradient from pressure, using a surgically placed tape to pull bladder to urethra and leads to urine leakage. the and urethra against the pubis.

Colposuspension is a procedure in which the In women, there have been significant lateral vaginal walls are attached to the prepubic complication rates with these procedures, tendon, thus drawing the bladder neck and frequently requiring removal of the tape. This proximal urethra further into the abdomen. This procedure has been adapted for use in dogs with has been found to have variable success (53%) some success; however, its use is not widespread. but has a high failure rate because of breakdown Concerns about similar complications to those of the attachment to the pelvic ligament. An seen in women may be partially responsible.23 11.3% complication rate has been reported Additional studies evaluating larger numbers related to urine retention and dysuria.20 of dogs and long-term followup are needed.

Urethropexy PREVENTION

Urethropexy repositions the bladder cranially Of course, the best management for UI would by anchoring the proximal urethra to the involve efforts to prevent it. It is well known prepubic tendon. Similar to colposuspension, that UI is most common in dogs that are spayed this increases transmission of intra-abdominal or neutered; however, the exact mechanism and pressure increases to the urethra as well as the relationship to estrogen and testosterone decline bladder and bladder neck, preventing a negative is unclear. A number of studies have evaluated the pressure gradient into the outflow tract. relationship of UI and age at spay or neuter. The results have been somewhat disparate, but there is Success has been reported to be similar to general agreement that the risk of UI increases if colposuspension, but with shorter efficacy, likely a female dog is spayed before 3 months of age. because of avulsion of the urethropexy from the prepubic tendon. Urethropexy may have an In a recent study, I found that the age of increased complication rate (21%) compared with ovariohysterectomy (OVH) did not appear to affect colposuspension, with surgical revision being risk of development of UI in dogs with an expected required in animals with urethral obstruction.21 adult weight of <15 kg. Smaller breeds are known to be at lower risk of urinary incontinence, and it Combined Urethropexy- appears that risk is not affected by age of spay. In Colposuspension larger breeds—dogs with an expected adult weight >15 kg—there is a decreased risk of UI with every A recent report of a combined technique of month delay in OVH. The larger the dog, the urethropexy and colposuspension revealed an more pronounced this alteration in risk becomes. improved success rate (70%) and durability compared with either procedure alone, as The decision of when to spay a dog can 22 well as fewer complications (10%). be challenging. The risks of delaying spay

26 URETHRAL INCOMPETENCE IN DOGS CONTINUING EDUCATION surgery, such as increased chance of mammary carcinoma, and benefits, like a lower risk Glossary of UI, should be openly discussed with the owner and tailored to the individual. DES diethylstilbestrol FSH follicle stimulating hormone Some evidence suggests that obesity may increase GnRH gonadotropin-releasing hormone the risk of incontinence in spayed female dogs; LH luteinizing hormone however, appropriate investigation into the OVH ovariohysterectomy contribution of body condition score is lacking. At this time, the contribution of obesity to the PPA phenylpropanolamine development of incontinence is unknown. UI urethral incompetence USMI urethral sphincter mechanism incompetence

REFERENCES

1. Byron JK, March PA, Chew DJ, DiBartola SP. Effect of phenylpropanolamine and pseudoephedrine on the urethral pressure profile and continence scores of incontinent female dogs. J Vet Intern 17. Byron JK, Chew DJ, McLoughlin ML. Retrospective evaluation of Med 2007;21(1):47-53. urethral bovine cross-linked collagen implantation for treatment of urinary incontinence in female dogs. J Vet Intern Med 2. Scott L, Leddy M, Bernay F, Davot JL. Evaluation of 2011;25(5):980-984. phenylpropanolamine in the treatment of urethral sphincter mechanism incompetence in the bitch. J Small Anim Pract 18. Rose SA, Adin CA, Ellison GW, et al. Long-term efficacy of a 2002;43(11):493-496. percutaneously adjustable hydraulic urethral sphincter for treatment of urinary incontinence in four dogs. Vet Surg 2009;38:747-753. 3. Peterson KL, Lee JA, Hovda LR. Phenylpropanolamine toxicosis in dogs: 170 cases (2004-2009). JAVMA 2011;239(11):1463-1469. 19. Reeves L, Adin C, McLoughlin M, et al. Outcome after placement of an artificial urethral sphincter in 27 dogs. Vet Surg 2013;42:12-18. 4. Segev G, Westropp JL, Kulik C, Lavy E. Changes in blood pressure following escalating doses of phenylpropanolamine and a suggested 20. Holt PE. Long-term evaluation of colposuspension in the treatment of protocol for monitoring. Can Vet J 2015;56(1):39-43. urinary incontinence due to incompetence of the urethral sphincter mechanism in the bitch. Vet Rec 1990;127(22):537-542. 5. Hill K, Jordan D, Ray J, et al. Medical therapy for acquired urinary incontinence in dogs. Int J Pharm Compd 2012;16(5):369-375. 21. White RN. Urethropexy for the management of urethral sphincter mechanism incompetence in the bitch. J Small Anim Pract 6. Kitta T, Haworth-Ward DJ, Miyazato M, et al. Effects of ovariectomy 2001;42(10):481-486. and estrogen replacement on the urethral continence reflex during sneezing in rats. J Urol 2011;186(4):1517-1523. 22. Martinoli S, Nelissen P, White RA. The outcome of combined urethropexy and colposuspension for management of bitches with 7. Dore M, Chevalier S, Sirois J. Estrogen-dependent induction urinary incontinence associated with urethral sphincter mechanism of cyclooxygenase-2 in the canine prostate in vivo. Vet Pathol incompetence. Vet Surg 2014;43(1):52-57. 2005;42(1):100-103. 23. Claeys S, de Leval J, Hamaide A. Transobturator vaginal tape inside 8. Sontas HB, Dokuzeylu B, Turna O, Ekici H. Estrogen-induced out for treatment of urethral sphincter mechanism incompetence: myelotoxicity in dogs: A review. Can Vet J 2009;50(10):1054-1058. preliminary results in 7 female dogs. Vet Surg 2010;39(8):969-979. 9. Nendick PA, Clark WT. Medical therapy of urinary incontinence in ovariectomised bitches: a comparison of the effectiveness of diethylstilboestrol and pseudoephedrine. Aust Vet J 1987;64(4):117-118. 10. Mandigers RJ, Nell T. Treatment of bitches with acquired urinary incontinence with oestriol. Vet Rec 2001;149(25):764-767. 11. Reichler IM, Hung E, Jochle W, et al. FSH and LH plasma levels Julie K. Byron in bitches with differences in risk for urinary incontinence. Julie K. Byron, DVM, MS, DACVIM, is an associate Theriogenology 2005;63(8):2164-2180. professor – clinical at The Ohio State University 12. Reichler IM, Jochle W, Piche CA, et al. Effect of a long acting GnRH College of Veterinary Medicine. Her primary area analogue or placebo on plasma LH/FSH, urethral pressure profiles of interest and research is lower urinary tract and clinical signs of urinary incontinence due to sphincter mechanism incompetence in bitches. Theriogenology 2006;66(5):1227-1236. disease, specifically urinary incontinence and functional obstruction. She has written more 13. Reichler IM, Hubler M, Jochle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. than 13 book chapters on the diagnosis and Theriogenology 2003;60(7):1207-1216. treatment of lower urinary tract disease, and 14. Creed KE. Effect of hormones on urethral sensitivity to phenylephrine she has authored numerous research articles on in normal and incontinent dogs. Res Vet Sci 1983;34(2):177-181. diagnosis and treatment of urinary incontinence. 15. Hamaide AJ, Grand JG, Farnir F, et al. Urodynamic and She received her veterinary degree in 1998 from morphologic changes in the lower portion of the urogenital tract The Ohio State University and completed a after administration of estriol alone and in combination with small animal internal medicine residency there phenylpropanolamine in sexually intact and spayed female dogs. Am J Vet Res 2006;67(5):901-908. in 2004. She has worked in both private and 16. Barth A, Reichler IM, Hubler M, et al. Evaluation of long-term effects academic practice and was a faculty member of endoscopic injection of collagen into the urethral submucosa for at the University of Illinois from 2005 to 2011. treatment of urethral sphincter incompetence in female dogs: 40 cases (1993-2000). JAVMA 2005;226(1):73-76.

MARCH/APRIL 2017 ■ TVPJOURNAL.COM 27 PEER REVIEWED Urethral Incompetence in Dogs: Updates in Management

TOPIC OVERVIEW The article you have read This article reviews the medical and surgical options available for treatment of urethral has been submitted for incompetence and provides guidelines to choosing the best one for each patient, as RACE approval for 1 hour of continuing education well as comments on prevention for potentially at-risk dogs. credit and will be opened for enrollment when approval LEARNING OBJECTIVES has been received. To receive • Practitioners will be able to describe the available medical therapies for treatment credit, take the approved test of urethral incompetence and the contraindications for each. online at vetmedteam.com/ • Practitioners will be able to describe the surgical options for treatment of urethral tvp.aspx (CE fee of $5/article). incompetence and the appropriate circumstances in which to choose them.

1. Which of the following medical therapies for 5. Which of the following surgical procedures UI would be the best first choice in a 10-year- appears to be the most durable? old, female spayed, mixed-breed dog with a. Colposuspension coexisting chronic kidney disease? b. Artificial urethral sphincter placement a. Estrogens c. Urethropexy b. Phenylpropanolamine d. Bulking therapy with bovine crosslinked c. Pseudoephedrine collagen d. GnRH analogs 6. Which of the following factors appears to 2. Which surgical therapy for UI is best suited for carry the most risk for development of UI? male dogs? a. Obesity a. Colposuspension b. Ovariohysterectomy after first estrus b. Urethral collagen injection c. Ovariohysterectomy before 3 months of c. Artificial urethral sphincter age d. Urethropexy d. Ovariohysterectomy after 1 litter

3. Which of the following is the best course of 7. Which of the following procedures is based action when a spayed female dog develops on the principle of increasing the stretch vulvar swelling while taking estriol? in the urethral sphincter muscles and a. Discontinue the medication and consider increasing resting closure pressure? surgical options a. Artificial urethral sphincter placement b. Discontinue estriol and start DES b. Colposuspension c. Reduce the dose of estriol and monitor for c. Urethropexy maintenance of continence d. Bulking therapy with injectable agents d. Add phenylpropanolamine to the estriol 8. A 9-year-old spayed female collie has been 4. A client brings their female spayed dog in for treated for UI with phenylpropanolamine a belated recheck 3 months after starting DES. (PPA) for 5 years. She has been having You discover the owner has not decreased the an increase in leakage events in the last 6 dose from the induction level of 1 mg/day. In months and has only partially improved with fact, the dog did not gain complete continence dose escalation. You are concerned about and the owner has increased the dose to further increasing the dose of PPA. Which of 3 mg/day for the last month. The dog is the following is the best next option? lethargic and has a decreased appetite. What is a. Add an estrogen to the PPA regimen the most important diagnostic test to perform b. Bulking therapy when looking for estrogen in this dog? c. Colposuspension a. Serum chemistry d. Artificial urethral sphincter placement b. Abdominal ultrasound c. Systolic blood pressure d. Complete blood count

28 URETHRAL INCOMPETENCE IN DOGS CONTINUING EDUCATION

9. Which of the following is the best medical therapy for male dogs with UI? a. Deslorelin acetate b. Testosterone cypionate c. Diethylstilbestrol (DES) d. Phenylpropanolamine (PPA)

10. Which two surgical procedures appear to have good success when combined in a patient with UI? a. Artificial urethral sphincter placement and bulking therapy b. Colposuspension and bulking therapy c. Colposuspension and urethropexy d. Urethropexy and bulking therapy

NOTE Questions online may differ from those here; answers are available once CE test is taken at vetmedteam.com/tvp.aspx. Tests are valid for 2 years from date of approval.

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