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Applications of Gnrh Immunization in Domestic Dogs

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Applications of Gnrh Immunization in Domestic Dogs AN ABSTRACT OF THE THESIS OF Caitlin Elizabeth Donovan for the degree of Master of Science in Animal Sciences presented on May 3, 2013 Title: Applications of GnRH Immunization in Domestic Dogs Abstract approved: Michelle Anne Kutzler Reproductive function in the dog is controlled by feedback mechanisms that involve the hypothalamus, the anterior pituitary gland, and the gonads. Surgical gonad removal, a common procedure performed in dogs for the purposes of sterilization, disrupts the hypothalamic-pituitary-gonadal (HPG) axis and results in permanently elevated concentrations of gonadotropins. Manipulation of the HPG axis via 19 gonadotropin releasing hormone (GnRH) immunization results in the synthesis of GnRH neutralizing antibodies, which bind to (neutralize) GnRH and prevent it from binding to its receptors. The end result of GnRH immunization is the cessation of pituitary gonadotropin secretion, namely luteinizing hormone (LH). In 2004, a commercial GnRH vaccine was launched in the United States (Canine Gonadotropin Releasing Factor Immunotherapeutic®; Pfizer Animal Health USA), labeled for the treatment of benign prostatic hyperplasia in intact male dogs. This research investigated two novel clinical applications of this vaccine in dogs. In the first study, physiologic responses to GnRH immunization in intact male dogs were observed. Four intact males were vaccinated with the GnRH vaccine twice at four week intervals. Blood samples were collected prior to each injection (at weeks 0 and 4) and at weeks 12 and 20 following initial vaccination. Scrotal measurements were also made at the time of each blood sample collection to calculate testicular volume. All four dogs developed a GnRH antibody titer and experienced a significant decrease in testosterone concentrations. Testicular volume also significantly decreased, and this effect was reversed by the end of the study. LH concentrations remained at basal levels. These results are indicative of temporary humoral response to the GnRH vaccine, and future studies should investigate prolonging these effects to potentiate GnRH immunization as a method of population control in dogs. Beyond use as a temporary immunosterilant, GnRH immunization has other promising clinical applications. Elevated gonadotropin concentrations as a result of 19 gonad removal in female dogs decreases urethral pressure, and in some bitches, this results in the development of urethral sphincter mechanism incompetence (USMI). Therefore, lowering gonadotropin concentrations in incontinent ovariectomized bitches through GnRH immunization may restore continence. In the second study, sixteen incontinent dogs that were using phenylpropanolamine (PPA) to control incontinence were recruited. Eleven dogs were immunized against GnRH at week 0, and nine dogs were vaccinated again four weeks later. Five control dogs were vaccinated with a placebo twice at four week intervals. Vaccinated dogs discontinued PPA two weeks after re- vaccination, and control dogs remained on PPA for the duration of the study. Blood samples were collected before each injection and at 6, 8, 10, 12, 16, 20, and 24 weeks, and owners recorded episodes of incontinence throughout the study. Of the nine dogs that completed the vaccination series, four dogs remained continent after PPA was discontinued. For these four dogs, there was no difference in the episodes of incontinence when using PPA versus treatment with the vaccine. All nine vaccinated dogs developed a GnRH antibody titer, and LH concentrations decreased significantly in vaccinated dogs compared to controls. These results indicate that decreasing LH concentrations through GnRH immunization restores continence to some, but not all incontinent ovariectomized bitches. Because the development of USMI results from decreased urethral pressure that happens after ovariectomy, future studies should focus on preventing this decrease in urethral pressure to prevent USMI from occurring. 19 ©Copyright by Caitlin Elizabeth Donovan May 3, 2013 All Rights Reserved 19 Applications of GnRH Immunization in Domestic Dogs by Caitlin Elizabeth Donovan A THESIS submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science 19 Presented May 3, 2013 Commencement June 2013 Master of Science thesis of Caitlin Elizabeth Donovan presented on May 3, 2013. APPROVED: Major Professor representing Animal Sciences Head of the Department of Animal and Rangeland Sciences Dean of the Graduate School I understand that my thesis will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my thesis to any reader upon request. 19 Caitlin Elizabeth Donovan, Author ACKNOWLEDGEMENTS I am so grateful to my advisor, Dr. Michelle Kutzler, for her unwavering support and guidance throughout my graduate career. Her incredible knowledge base, experience, and ability to provoke me to think outside of the box has truly helped me become the researcher I am today, and her drive has pushed me to accomplish very much in a short amount of time. I am so thankful that I had the opportunity to learn from her. I also want to thank Dr. Jana Gordon for all her help with the urinary incontinence study and Dr. Tim Hazzard for teaching me how to be a conscientious researcher. Both individuals provided excellent insight for the project, and I am immensely appreciative of their ideas, guidance, and support. I am also hugely indebted for the support and friendship of the Theriogenology Laboratory: Laura Sahlfeld, Libby Fellows, and Justine Gullaba. Various people at Oregon State University and the surrounding community have been an immense help to me. Thank you to Dr. Gerd Bobe for numerous lessons in statistics, Meredith Hanson and Jennifer Gartner for always being available to help me out with the study dogs, Reni Stewart for her incredible ability to recruit dogs at the drop of a hat, and the owners and their dogs that participated in the study. Without these people, this study would not have been possible. Thank you so much to the Department of Animal and Rangeland Sciences for granting me an assistantship, the Collie Health Foundation for funding the urinary incontinence study, and 19 Pfizer Animal Health for product donation. Also, a huge thank you to my other fellow co-authors I have worked with over the last two years on various projects; Marty Greer, Katherine Peed, Jennifer Grossman, Kristin Patton, Steve Lamb, Tessa Fiamengo, Andy Schmidt, JoAnne Lemieux, and Frances Hathaway. My family has always done everything in their power to be there for me, and I cannot thank them enough for helping me to always be the best I can be. Moving across the country to come to Oregon State was a big change, but their unwavering encouragement to follow my dreams has allowed me to be successful. I truly have the best family anyone could ask for. Finally, I would not be here today without the support of my boyfriend Arthur. He has been my foundation through this chapter of my life, and I look forward to the beginning of a new chapter as we head on to Davis, California so I can pursue my doctorate. 19 CONTRIBUTIONS OF AUTHORS Dr. Michelle Kutzler conceptualized, provided oversight, and edited the manuscripts for the male dog and incontinence study. Dr. Marty Greer assisted with male dog sample collection and edited the resulting manuscript. Dr. Jana Gordon helped conceptualize the incontinence study, assisted with incontinent dog sample collection, and edited the resulting manuscript. Katherine Peed assisted with research initiation of the male dog study, and Dr. Tim Hazzard assisted with assay preparation in the male dog study. 19 TABLE OF CONTENTS Page 1 INTRODUCTION ................................................................................................................. 1 1.1 The Hypothalamic-Pituitary-Gonadal Axis in the Bitch .......................................... 1 1.1.1 Summary ............................................................................................... 1 1.1.2 Gonadotropin-Releasing Hormone ....................................................... 1 1.1.3 Gonadotropins ....................................................................................... 2 1.1.4 Gonadal Feedback ................................................................................ 3 1.1.5 HPG Axis in the Intact Bitch ................................................................ 5 1.1.6 HPG Axis in the Ovariectomized Bitch ................................................ 6 1.2 Nonclassical Actions of GnRH, LH, and FSH in the Bitch ..................................... 7 1.2.1 Summary ............................................................................................... 7 1.2.2 Action on the Skin ................................................................................ 7 1.2.3 Action on the Urinary Bladder and Urethra .......................................... 9 1.2.4 Conclusions ........................................................................................... 10 1.3 Applications of GnRH Analogues and Immunization .............................................. 11 1.3.1 Summary ............................................................................................... 11 1.3.2 GnRH Agonists ..................................................................................... 11 1.3.3 GnRH Antagonists ................................................................................ 14 1.3.4 Immunization
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