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Reversible Downregulation of Hypothalamic-Pituitary-Gonadal Axis in the Stallion with a Third-Generation Gnrh Antagonist" (2015)

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Reversible Downregulation of Hypothalamic-Pituitary-Gonadal Axis in the Stallion with a Third-Generation Gnrh Antagonist University of Kentucky UKnowledge Theses and Dissertations--Veterinary Science Veterinary Science 2015 REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC- PITUITARY-GONADAL AXIS IN THE STALLION WITH A THIRD- GENERATION GNRH ANTAGONIST Gabriel Monteiro Davolli University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Monteiro Davolli, Gabriel, "REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC-PITUITARY-GONADAL AXIS IN THE STALLION WITH A THIRD-GENERATION GNRH ANTAGONIST" (2015). Theses and Dissertations--Veterinary Science. 22. https://uknowledge.uky.edu/gluck_etds/22 This Master's Thesis is brought to you for free and open access by the Veterinary Science at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Veterinary Science by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Gabriel Monteiro Davolli, Student Dr. Edward L. Squires, Major Professor Dr. Daniel K. Howe, Director of Graduate Studies REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC-PITUITARY- GONADAL AXIS IN THE STALLION WITH A THIRD-GENERATION GNRH ANTAGONIST __________________________________________________ THESIS __________________________________________________ A thesis submitted in partial fulfillment of the requirements for the degree of Master in Science in the College of Agriculture, Food and Environment at the University of Kentucky By Gabriel Monteiro Davolli Lexington, Kentucky Director of thesis: Dr. Edward L. Squires Lexington, Kentucky 2015 ABSTRACT OF THESIS REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC-PITUITARY- GONADAL AXIS IN THE STALLION WITH A THIRD-GENERATION GNRH ANTAGONIST The objectives of this thesis were: (1) to evaluate the downregulation of the stallion hypothalamic-pituitary-gonadal (HPG) axis by a GnRH antagonist (acyline) based upon endocrine, seminal, testicular and behavioral effects, and (2) to assess recovery after treatment. Stallions were treated for 50 days (n=4; 330µg/kg acyline q 5d) and controls (n=4) received vehicle alone. Stallions were assessed pre-treatment and for 72 days after last treatment. Treatment induced declines (p<0.05) in FSH, LH, testosterone (to castrate levels) and estrone sulfate. Gonadotropins and testosterone returned to control values within nine days and estrone sulfate by 14 days after treatment discontinuation. Acyline- treated stallions failed to respond with FSH, LH and testosterone increase after exogenous GnRH stimulation (25µg gonadorelin, IV) compared to pre-treatment and control stimulation. Total sperm numbers and motility were reduced in acyline-treated stallions, as well as total seminal plasma protein and testicular volume (p<0.05). Time to ejaculation was increased in acyline group (p<0.5). Testicular, sexual behavior and most seminal parameters regained normal levels within 72 days after treatment ceased. Sperm output of acyline-treated stallions was regained within seven months after ending treatment. Acyline reversibly suppressed the stallion HPG axis, thus has potential for treating the androgen- dependent Equine-Arteritis-Virus carrier state and as behavior modulator. KEYWORDS: Hypothalamic-pituitary-gonadal axis, GnRH antagonist, Stallion, Equine Arteritis Virus (EAV), Sexual Behavior. i REVERSIBLE DOWNREGULATION OF HYPOTHALAMIC-PITUITARY- GONADAL AXIS IN THE STALLION WITH A THIRD-GENERATION GNRH ANTAGONIST By Gabriel Monteiro Davolli Dr. Edward L. Squires Director of Thesis Dr. Daniel K. Howe Director of Graduate Studies 2/05/2015 ii Acknowledgements I will always carry an immeasurable gratitude to my loving parents, Isabel and Américo, who valued the education of their children above everything. They also gave me my sister, Leticia, who is a treasure that I have for life; a light shining bright whenever I need advice. I almost felt like it was cheating for having the distinguished professors of my committee: Drs. Ed Squires, Barry Ball, Mats Troedsson and Peter Timoney. The combination of your varying approaches to the matter being investigated can only be beneficial for somebody willing to learn. Dr. Ball was always available to patiently aid me in the different aspects of the investigation that I was involved with during the Master’s, related or not to this project; I am immensely grateful for that. My academic advisor, Dr. Squires was essential in designing the project, assuring that the execution was proper and reviewing this thesis while keeping me in the right track. I am grateful for the big help and the flexibility to get it done. I owe to Dr. Troedsson’s kindness and support the opportunity to first visit the Gluck Center and meet Central Kentucky, and, later, to join the graduate program at Veterinary Science. The inputs from Dr. Troedsson and Dr. Timoney in the planning of this research project and counseling during the process were very important so it could get done; right. In the Reproduction laboratory, I have the luck to consider some folks more friends of mine than co-workers. Biggest thanks to my buddy, Carleigh Fedorka, who has been a very good companion through all this journey and on whom I could rely to help me throughout the collection of all my data. Dr. Anthony Claes played a crucial part during the execution of this project and was somebody to look up to and to get advice from during the entire duration of the project. Dr. Alejandro Esteller-Vico, always with available time iii and patience, also positively impacted the data collection and, unwinding the various steps of its analysis, was a very reliable source of knowledge. Dr. Kirsten Scoggin is one of the most efficient persons that I have had the luck to work with; I am very grateful for her tackling all kinds of technical and logistical tasks. I would like to thank Dr. Elizabeth Woodward for the advices and example of great perseverance. Dr. Igor Canisso gave me a good hand and insights during the process. Dr. Abdo Alghamdi with his investigative eye and good humor was a skillful hand and mind that I had the luck to have available for free – what a bargain! Jackie Barr, Michelle Gruss and Dr. Nathaniel Newton were very handy in assisting with the data collection for this project. I would not have had the chance to start in this program without the previous basis on Equine Reproduction, both clinically and research inclined, received from my mentor Dr. Rodrigo Mattos, back in Rio Grande do Sul. Dr. Maria Inês Jobim also influenced me positively in order to grow my interest on research in animal reproduction. I owe a great deal to Dr. Gustavo Winter for sharing his clinical experience with me through various breeding seasons and emphasizing the importance of allying the knowledge obtained from research and clinical experience for a better outcome when in practice. Finally, Dr. Ivan Bustamante’s passion as an innate researcher allowed me to appreciate in depth research and probably hastened my pursuit to embark in a closer involvement with investigation. iv Table of Contents Acknowledgements ............................................................................................................ iii List of tables ...................................................................................................................... vii List of Figures .................................................................................................................. viii Chapter One: Introduction .............................................................................................. 1 Chapter Two: Literature Review ................................................................................... 3 2. Manipulation the Hypothalamic-pituitary-gonadal (HPG) axis ..................................... 3 2.1. Justifications for interference of reproductive endocrine function in stallions ............ 3 2.1.1 Equine Viral Arteritis .............................................................................................. 3 A. History,
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