Journal of Veterinary Science & Medical Diagnosis ISSN: 2325-9590

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Case Report, J Vet Sci Med Diagn Vol: 2 Issue: 3

Gonadotropin-Releasing Hormone Immunization to Treat Urethral Sphincter Mechanism Incompetence in a Bitch that Experienced an Adverse Reaction to Phenylpropanolamine

CE Donovan1, A Weston2 and MA Kutzler1*
1Department of Animal and Rangeland Sciences, Oregon State University, Corvallis, OR, USA
2Town and Country Animal Clinic, Corvallis, OR, USA
Corresponding author : Michelle Kutzler
312 Withycombe Hall, Oregon State University, Corvallis OR 97331, USA
E-mail: [email protected]
Received: July 19, 2013 Accepted: September 25, 2013 Published: September 30, 2013
Citation: Donovan CE, Weston A, Kutzler MA (2013) Gonadotropin-Releasing Hormone Immunization to Treat Urethral Sphincter Mechanism Incompetence in a Bitch that Experienced an Adverse Reaction to Phenylpropanolamine. J Vet Sci Med Diagn 2:3. doi:10.4172/2325-9590.1000119

Abstract

Gonadotropin-Releasing Hormone Immunization to Treat Urethral Sphincter Mechanism Incompetence in a Bitch that Experienced an Adverse Reaction to Phenylpropanolamine

A 12 year old spayed female Queensland heeler mix was presented for the evaluation of unconscious urine leakage that occurred when the dog was sleeping. Urinalysis revealed no abnormalities and the dog was diagnosed with urethral sphincter mechanism incompetence. Phenylpropanolamine was prescribed and resolved incontinence but resulted in lethargy, anxiety, and nasal and ocular discharge. Discontinuation of phenylpropanolamine resolved these symptoms, but incontinence recurred. The dog was then treated by immunizing against GnRH.

Keywords: GnRH immunization; Dog; Phenylpropanolamine; Urinary incontinence; Ovariectomy; Ovariohysterectomy

 

Keywords

GnRH immunization; Dog; Phenylpropanolamine; Urinary incontinence; Ovariectomy; Ovariohysterectomy

Introduction

The development of urethral sphincter mechanism incompetence (USMI) in female dogs is not uncommon following ovariectomy or ovariohysterectomy, with incidences reported between 5.7-20% in spayed bitches [1,2]. The condition can develop immediately or years after surgery [1]. Spayed dogs experience a decrease in urethral closure pressure after surgery [3], and dogs that develop USMI experience an even further reduction in pressure [4]. Because urethral closure pressure is normally maintained by sympathetic activation of α1 adrenoreceptors in the urethral smooth muscle [5], the most common current method of treating USMI is with α-adrenergic agonists, specifically phenylpropanolamine (PPA) [6]. PPA mimics the effects of catecholamines by activating α1 adrenoreceptors present in urethral smooth muscle, increasing urethral pressure and restoring continence. However, side effects of PPA administration can manifest due to the presence of α1 adrenoreceptors elsewhere in the body. Side effects reported in the dog include hypertension, anorexia, restlessness, emesis, weight loss, lethargy, behavior changes, and proteinuria [7,8].
Because USMI manifests mainly as a result of spaying, it has been postulated that elevated gonadotropin concentrations that occur as a result of ovary removal contribute to the development of USMI [9]. It has been shown that decreasing gonadotropin concentrations through the use of gonadotropin-releasing hormone (GnRH) agonists can restore continence to incontinent spayed dogs [9,10]. Long-term administration of a GnRH agonist results in downregulation of GnRH receptors in the pituitary, and this desensitization results in a sharp drop of gonadotropin concentrations to basal levels [9].
Unfortunately, GnRH agonist availability is limited in the United States. To date, deslorelin acetate (Suprelorin, Virbac Animal Health, Fort Worth, TX, USA) is the only GnRH agonist that has been developed for use in domestic animals [11]; however, it is currently available in the United States only for the treatment of adrenal disease in ferrets and extra-label use is explicitly prohibited [12].
An alternative option available in the United States, immunization against GnRH, has been shown to reduce steroid hormone production through decreasing gonadotropin concentrations in intact male dogs [13]. The purpose of this paper is to report on an alternative method (GnRH immunization) to treat USMI in a spayed dog that experienced adverse side effects to the conventional treatment of PPA.

Case Report

A twelve-year-old, 17 kg, spayed female Queensland heeler mix was presented for evaluation of unconscious urine leakage that occurred when the dog was sleeping. Incontinence had been occurring daily for approximately one week before the dog was presented. A physical exam was completed and all parameters were found to be within normal limits. Urine was obtained by free catch and urinalysis revealed no abnormalities. A diagnosis of USMI was made and treatment with phenylpropanolamine (Proin®, PRN Pharmacal, Pensacola, FL, USA; 1.5 mg/kg body weight, q 12 hours per os [PO]) was initiated. No further investigations were performed.
After 48 hours of treatment, the owners reported that urine leakage had stopped but the dog was restless, so the PPA dose was decreased (0.75 mg/kg body weight, q 12 hours PO). After another 48 hours of treatment at the decreased dose, the owners continued to report restlessness as well as lethargy, anxiety, and ocular and nasal discharge. PPA was discontinued and the dog was presented for examination 48 hours later. Bilateral nasal and ocular discharge and bilateral reddened sclera were observed upon physical examination. Temperature, heart rate, and respiration were within normal limits. The patient was discharged with instructions for the owner to monitor the dog’s condition and to return if symptoms worsened or persisted. The owner reported that the following day, the dog’s behavior had returned to normal and ocular and nasal discharge had ceased.
The dog was re-evaluated for an alternative USMI treatment six days after she had recovered from the adverse reaction to PPA as urine leakage had resumed. The owners of the dog were presented with the option of immunizing against GnRH, which was an available treatment at the veterinary clinic at the time. The procedure consisted of an initial vaccine followed by a booster vaccine given 28 days later. While the duration of the efficacious effect was unknown, the owners were told it would be temporary. They were also informed that a latency period was to be expected for sufficient antibody development. The owners opted to proceed with the treatment and the dog was immunized against GnRH (Canine Gonadotropin Releasing Factor Immunotherapeutic, Pfizer Animal Health, Exton, PA, USA; 1 mL subcutaneously [SC] at the lateral thorax q 28 days). After initial vaccination, the owners reported tachypnea, restlessness, anxiety, complete anorexia, refusal to drink water, and soreness at the injection site. These symptoms resolved completely without treatment 24 hours after initial vaccination. Urine leakage stopped 23 days later, and the owners opted to proceed with the booster injection 28 days after the initial vaccination as scheduled. The booster vaccine (1 mL SC) was administered at the left scapula in conjunction with diphenhydramine (2 mg/kg SC at the right scapula) to minimize adverse effects. After vaccination, the owners reported lethargy that resolved 24 hours after vaccination.
The dog did not experience any urine leakage for 25 weeks. Ten days after leaking had resumed again, the dog received diphenhydramine (2 mg/kg SC at the right scapula) and was re-vaccinated against GnRH (1 mL SC at the left scapula) 30 minutes later. The owners reported lethargic behavior the afternoon after vaccination and no further urine leakage. At the time of writing this case report, 20 weeks after the third vaccination, the dog is still continent.

Discussion

The dog described in this case report experiencing episodes of urinary incontinence responded adversely to PPA, a widelyprescribed treatment for USMI [14]. While incontinent episodes ceased while PPA was being administered, side effects the dog experienced were not tolerable and as a result, a non-conventional treatment, immunization against GnRH, was initiated. While the dog responded adversely to the first immunization, administering later immunizations with diphenhydramine greatly reduced adverse effects. Furthermore, GnRH immunization was effectively able to restore continence in this dog.
There are considerable abnormalities or conditions that can result in unwanted urinary leakage. While USMI is the most common cause of urinary incontinence secondary to ovariectomy, it is largely diagnosed based upon exclusion of other possibilities [15]. It is affordable for a dog owner and easy for a veterinary clinic to immediately eliminate a urinary tract infection as a possible cause of urine leakage. If cost is not a factor in further diagnostic work, radiography and/or ultrasound can be utilized to eliminate any anatomic abnormalities [16]. In cases where USMI is likely, urethral pressure profilometry can be performed to confirm the diagnosis [16]. Arnold et al. [3] reported that a urethral closure pressure of less than 7.4 cm H2O allowed for the differentiation of bitches with USMI with a diagnostic accuracy of 91%. However, the cost of these diagnostic procedures is a limiting factor for a majority of dog owners. As a result, it is likely in the field that a diagnosis of USMI relies considerably on typical clinical signs and history of incontinent episodes [14,15]. In this case, congenital abnormalities were unlikely because the dog was older and had not been incontinent prior to presentation. Furthermore, the dog was only experiencing episodes of incontinence while asleep, a typical clinical sign of USMI [17]. Given the dog’s history and cost of diagnostic treatments being a limiting factor, it was decided to treat the dog using a conventional USMI treatment and assess the efficacy of the treatment in diminishing clinical signs. Treatment with PPA did result in cessation of incontinent episodes, further indicating that an incompetent urethral sphincter was likely the cause of urine leakage.
PPA is the drug therapy of choice by most veterinarians for dogs diagnosed with USMI as it effectively increases urethral closure pressure and restores continence in a majority of cases [4,14]. However, PPA is not effective in all cases of USMI. This treatment is estimated to be ineffective in approximately 10-15% of affected dogs [4,14,18,19]. Furthermore, adverse effects, including restlessness, lethargy, behavior changes, anorexia, weight loss, emesis, hypertension, and proteinuria [7,8], can prevent PPA from being an appropriate therapy in some cases. While PPA effectively prevented episodes of incontinence in the dog presented in this case report, adverse effects prompted investigation into an alternative treatment.
The GnRH vaccine used in this study is labeled for the treatment of benign prostatic hyperplasia in intact male dogs, an androgendependent condition [20]. By eliciting antibodies against GnRH, the vaccine is effectively able to decrease gonadotropin concentrations, which in turn reduce androgen production. Given that elevated gonadotropins as a result of spaying have been postulated to contribute to the development of urinary incontinence [9], reducing gonadotropins using this vaccine may also serve as a treatment for dogs with USMI. This vaccine was able to effectively restore continence in the dog in this study for 25 weeks.
Side effects of the vaccine were experienced by the dog after initial vaccination; administration of diphenhydramine with the second and third vaccination significantly minimized observed side effects. Safety of the vaccine by the manufacturer at 1 mL (n=237) and 2 mL (n=24) doses was reported in intact male dogs with no significant adverse events observed [20]. However, mild injection site swelling occurred in 10% of the intact male dogs at the 1 mL dose and in 8.3% of the intact male dogs at the 2 mL dose. Minor side effects were also reported when the vaccine was used for pregnancy termination in bitches [21].
An alternative treatment option besides PPA for dogs with USMI does exist; estrogens increase urethral closure pressure by increasing receptor sensitivity to catecholamines [22], thereby effectively treating USMI in some cases. In the past, diethylstilbestrol (DES) was the estrogen of choice for dogs with USMI [23]; however, this estrogen is not FDA approved for the treatment of USMI in the United States and therefore has to be obtained through compounding pharmacies. Furthermore, canine bone marrow is exquisitely sensitive to the suppressive effects of estrogens [24], resulting in a narrow therapeutic window. However, daily treatment with estriol (Incurin®, Merck Animal Health), a shorter-acting estrogen, has recently received FDA approval for the treatment of urinary incontinence. Regardless, estrogen therapy is effective in approximately 50-65% of cases [25-27] and can result in signs of estrus. While combination therapies, specifically PPA paired with an estrogen, are another option for USMI treatment when neither is effective alone, cases exist where even combination therapy does not completely restore continence [28].
It is necessary to identify and provide more effective therapy options for USMI for cases where PPA and/or estrogens are not suitable treatments. While decreasing gonadotropins through the use of long-acting GnRH agonists alone have been shown to be efficacious in approximately 50% of cases [9,10], using GnRH agonists as part of a combination therapy have been identified as an effective alternative option. In a study where neither PPA nor GnRH agonists were completely effective in restoring continence alone, the combination of the two therapies safely restored continence completely in 5/6 treated dogs [9]. This further highlights the clinical relevance of decreasing gonadotropin concentrations for the treatment of USMI.
No therapy currently available for USMI is completely effective at restoring continence. This case report exemplifies the need for alternative therapies for USMI when PPA results in adverse side effects that cannot be tolerated by the dog or the owner. Immunization against GnRH, administered in conjunction with diphenhydramine, effectively restored continence in the dog for a prolonged duration with minimal injection site side effects.

Acknowledgement

The authors sincerely appreciate Pfizer Animal Health for product donation and the Collie Heath Foundation for funding. We also thank the staff at Town and Country Animal Clinic for technical assistance.

Conflict of Interest

The authors declare no conflicts of interest.

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