Contraception and Fertility Control in Dogs and Cats - Alliance for

154 Pages·2013·1.81 MB·English

Contraception and
Fertility Control in
Dogs and Cats
A Report of the Alliance for
Contraception in Cats & Dogs (ACC&D)
February 2013
C©o n2t0ra1c3e.p Atiolln r aignhd tFse rrteislietyr vCeodn.trol in Dogs and Cats 1
Table Of Contents
Dedication .........................................................................................................................................8
Preface ...............................................................................................................................................9
1.0 Introduction ...........................................................................................................................11
1.1 Scope of the Report .....................................................................................................................11
1.2 Brief Review of the Historical Context of Contraception and
Fertility Control Research in Animals ...........................................................................................11
1.3 Targets and Historical Approaches to Non-Surgical Sterilization in Dogs and Cats ....................12
1.4 Considerations for Commercializable Approaches to Non-Surgical Contraceptive Methods ......16
2.0 The Physiology of Reproductive Control in Mammals –
Overview of the Major Systems that Control Reproduction .............................................17
2.1 Brain .............................................................................................................................................17
2.2 Pituitary .......................................................................................................................................17
2.3 Gonads (Ovaries and Testes) ........................................................................................................17
2.4 Unique Aspects of Canine and Feline Reproductive Biology .........................................................17
3.0 Overview of Technological Approaches and Their Applications in Dogs and Cats .........19
3.1 Surgical Approaches .....................................................................................................................19
3.1.1 Overview ................................................................................................................................................19
3.1.2 Surgical Methodologies ..........................................................................................................................22
3.1.2.1 Females .........................................................................................................................................22
3.1.2.2 Males ............................................................................................................................................22
3.2 Gonadotropin-Releasing Hormone (GnRH) ....................................................................................23
3.2.1 Overview of GnRH Agonists .......................................................................................................................23
3.2.1.1 Deslorelin .............................................................................................................................................24
3.2.1.1.1 Deslorelin in Dogs – Males ...............................................................................................................24
3.2.1.1.2 Deslorelin in Dogs – Females ..........................................................................................................25
3.2.1.1.3 Deslorelin in Cats – Toms ...............................................................................................................26
3.2.1.1.4 Deslorelin in Cats – Queens ............................................................................................................27
3.2.1.1.5 Recently Reported Research Involving the Use of Deslorelin for Contraception .................................28
3.2.1.2 Nafarelin ..............................................................................................................................................29
3.2.1.2.1 Nafarelin in Dogs ...........................................................................................................................29
3.2.1.2.2 Nafarelin in Cats ............................................................................................................................30
3.2.1.3 Other GnRH Agonists ............................................................................................................................30
3.2.1.4 GnRH Agonists: Summary of Advantages and Disadvantages ..................................................................30
3.2.2 Overview of GnRH Antagonists ..................................................................................................................31
3.2.2.1 GnRH Antagonist Peptides .....................................................................................................................31
3.2.2.2 Non-Peptide GnRH Antagonists .............................................................................................................32
3.2.2.3 GnRH Antagonist in Dogs ......................................................................................................................32
3.2.2.3.1 Males ..............................................................................................................................................32
3.2.2.3.2 Females ...........................................................................................................................................33
Contraception and Fertility Control in Dogs and Cats 2
3.2.2.4 GnRH Antagonists in Cats ..............................................................................................................33
3.2.2.5 GnRH Antagonists: Summary of Advantages and Disadvantages ......................................................34
3.2.3 Overview of GnRH-Toxin Conjugates .......................................................................................................35
3.2.3.1 GnRH-Protein Synthesis Inhibitor Conjugate ...................................................................................35
3.2.4 Overview of GnRH Vaccines ....................................................................................................................36
3.2.4.1 GnRH Vaccines in Dogs .................................................................................................................38
3.2.4.2 GnRH Vaccines in Cats ...................................................................................................................40
3.2.4.3 GnRH Vaccines: Summary of Advantages and Disadvantages ...........................................................42
3.3 Other Vaccine Approaches ................................................................................................................43
3.3.1 Zona Pellucida (ZP) and Egg and Sperm Vaccines .....................................................................................43
3.3.1.1 Overview .......................................................................................................................................43
3.3.1.2 ZP Vaccines ....................................................................................................................................43
3.3.1.2.1 ZP in Dogs ................................................................................................................................44
3.3.1.2.2 ZP in Cats .................................................................................................................................45
3.3.1.2.3 ZP Vaccines: Summary of Advantages and Disadvantages ...........................................................47
3.3.1.3 Vaccination against Egg and Sperm Proteins ........................................................................................47
3.3.1.3.1 Vaccination against Egg Proteins ...............................................................................................47
3.3.1.3.2 Vaccination against Sperm Proteins ...........................................................................................48
3.3.1.3.3 Egg and Sperm Proteins: Summary of Advantages and Disadvantages ........................................49
3.3.2 Luteinizing Hormone (LH) Receptor Vaccines ...........................................................................................49
3.3.2.1 LH Receptor Vaccines: Summary of Advantages and Disadvantages .................................................49
3.4 Chemical Sterilants ...........................................................................................................................50
3.4.1 Zinc Gluconate ...........................................................................................................................................50
3.4.1.1 Zinc Gluconate in Dogs ..................................................................................................................51
3.4.1.2 Zinc Gluconate in Cats ...................................................................................................................52
3.4.2 Calcium Chloride ....................................................................................................................................52
3.4.2.1 Calcium Chloride in Dogs ...............................................................................................................52
3.4.2.2 Calcium Chloride in Cats ................................................................................................................53
3.4.3 Chlorhexidine Digluconate .........................................................................................................................53
3.4.4 Vinylcyclohexene Diepoxide ....................................................................................................................54
3.4.5 Hypertonic Saline ....................................................................................................................................54
3.4.6 Chemical Sterilants: Summary of Advantages and Disadvantages .............................................................55
3.5 Sex Steroids .................................................................................................................................55
3.5.1 Progestins ..............................................................................................................................................55
3.5.1.1 Bitches and Queens........................................................................................................................56
3.5.1.2 Male Dogs and Cats .......................................................................................................................57
3.5.2 Androgens .............................................................................................................................................57
3.5.3 Anti-Androgens, Anti-Estrogens and Aromatase Inhibitors .......................................................................58
3.5.4 Progestational and Androgenic Drugs: Summary of Advantages and Disadvantages .................................58
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3.6 Miscellaneous Research of Interest .............................................................................................58
3.6.1 Gene Silencing .......................................................................................................................................58
3.6.2 Kisspeptin and Gonadotropin-Inhibitory Hormone (GnIH) ........................................................................59
3.6.3 Egg Proteins and Peptides ......................................................................................................................59
3.6.4 Targeted Delivery of Cytotoxins ...............................................................................................................61
3.6.4.1 Single-Dose Non-Hormonal Male and Female Sterilant ....................................................................61
3.6.4.2 FSH Receptor Ligand-Cytotoxin Conjugates.....................................................................................61
3.6.4.3 Reversible Inhibition of Sperm under Guidance (RISUG) ..................................................................61
3.6.5 Retinoic Acid Receptor Antagonists .........................................................................................................62
3.6.6 Sperm Protein Reactive with Antisperm Antibodies (SPRASA) ...................................................................62
4.0 Overview of Companies, Organizations, Institutions, and Agencies Involved
in Researching or Developing Approaches to Non-Surgical Contraception
in Dogs and Cats .....................................................................................................63
4.1 Setting the Framework: Overview of Existing Non-Surgical Products ........................................63
4.2 Companies ...................................................................................................................................64
4.2.1 Major Animal Health Companies .............................................................................................................64
4.2.1.1 Historical Involvement ....................................................................................................................65
4.2.1.2 Virbac Acquisition of Peptech Animal Health (Suprelorin) .................................................................66
4.2.2 Smaller Companies .................................................................................................................................66
4.2.3 Update on Entities Profiled in the 2002 Report ........................................................................................66
4.2.4 Companies Currently or Recently Involved in Non-Surgical Contraception and Fertility
Control for Dogs and/or Cats ..................................................................................................................69
4.2.4.1 Amplicon Vaccine, LLC, Pullman, WA ...............................................................................................69
4.2.4.2 Ark Sciences, Inc., New York, NY .....................................................................................................69
4.2.4.3 Crinetics Pharmaceuticals, Inc., San Diego, CA ................................................................................69
4.2.4.4 FeralStat, Old Lyme, CT ...................................................................................................................69
4.2.4.5 Rhobifarma Industria Farmaceutica Ltda, Brazil ...............................................................................70
4.2.4.6 SenesTech, Inc., Flagstaff, AZ ..........................................................................................................70
4.2.4.7 Vaxin, Inc., Birmingham, AL ............................................................................................................71
4.3 Research: Organizations and Foundations, Government Agencies, and Academic and
Research Institutions ...................................................................................................................71
4.3.1 Update on Research Described in the 2002 Report ..................................................................................72
4.3.2 Universities Working on Non-Surgical Approaches ...................................................................................75
4.3.3 Organizations and Foundations ...............................................................................................................77
4.3.3.1 Alliance for Contraception in Cats & Dogs, Portland, OR ..................................................................78
4.3.3.1.1 ACC&D Symposia ......................................................................................................................78
4.3.3.1.2 ACC&D Think Tanks ...................................................................................................................78
4.3.3.1.3 ACC&D-Sponsored Studies ........................................................................................................79
4.3.3.2 Found Animals Foundation/Michelson Prize & Grants in Reproductive Biology, Los Angeles, CA ........79
4.3.3.3 Morris Animal Foundation, Denver, CO ............................................................................................82
4.3.3.4 Parsemus Foundation, San Francisco, CA .........................................................................................83
4.3.3.5 600 Million Stray Dogs Need You, Pompano Beach, FL ....................................................................83
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4.3.4 Government ...........................................................................................................................................84
4.3.4.1 United States Department of Agriculture National Wildlife Research Center, Fort Collins, CO ............84
4.3.4.2 United States Centers for Disease Control and Prevention, Atlanta, GA ............................................84
4.3.4.3 Cooperative Research Centres, Australia .........................................................................................85
4.3.4.4 AFSSA Nancy, Wildlife Health and Management Unit, Malzéville, France ..........................................85
4.3.4.5 Food and Environment Research Agency, United Kingdom ...............................................................85
4.3.4.6 The AZA Wildlife Contraception Center, St. Louis, MO ......................................................................86
5.0 Marketing Overview and Issues .................................................................................87
5.1 Overview ...........................................................................................................................................87
5.2 “Owned” Dogs and Cats ....................................................................................................................89
5.2.1 Population and Spending Estimates ........................................................................................................90
5.2.1.1 North America ...............................................................................................................................90
5.2.1.1.1 United States ............................................................................................................................90
5.2.1.1.2 Canada ....................................................................................................................................94
5.2.1.2 Outside of North America ..............................................................................................................94
5.2.1.2.1 Europe ......................................................................................................................................94
5.2.1.2.1.1 United Kingdom ...................................................................................................................95
5.2.1.2.1.2 France ..................................................................................................................................95
5.2.1.2.1.3 Germany ..............................................................................................................................95
5.2.1.3 Cat and Dog Populations vis-a-vis Human Populations: Europe and US ...........................................96
5.2.1.4 Other Areas...................................................................................................................................97
5.2.1.4.1 Australia ...................................................................................................................................97
5.2.1.4.2 Asia (Japan and China) .............................................................................................................97
5.2.1.4.2.1 Japan ...................................................................................................................................97
5.2.1.4.2.2 China ...................................................................................................................................98
5.2.1.4.3 Latin America ............................................................................................................................98
5.2.2 Dynamics of the Spay/Neuter Decision ........................................................................................................99
5.2.2.1 Summary of Pros and Cons of Spay or Castration in Dogs and Cats .................................................99
5.2.2.2 What Drives Owners’ Decisions and What Are Some Statistics? .....................................................100
5.2.2.2.1 In the United States ................................................................................................................100
5.2.2.2.1.1 Legislation .........................................................................................................................104
Sidebar: Estimated Size of the US Market for Sterilization of Dogs and Cats ...........................................104
5.2.2.2.1.2 Economic/Price Sensitivity ...................................................................................................105
5.2.2.2.2 Outside the United States ........................................................................................................105
5.2.2.3 A Sample of Spay/Neuter Costs ....................................................................................................108
5.3 Show Animal Owners and Dog and Cat Breeders ............................................................................112
5.4 “Unowned” Dogs and Cats ..............................................................................................................112
5.4.1 Dealing with “Free-Roaming” Animals ......................................................................................................116
5.4.1.1 A Look at Methods of Dealing with Free-Roaming Dogs .....................................................................116
5.4.1.2 A Look at Methods of Dealing with Free-Roaming Cats ......................................................................117
Contraception and Fertility Control in Dogs and Cats 5
5.4.1.3 Advocacy and Population Management Projects Utilizing Non-Surgical Methodology: Lessons Learned 119
5.5 “Shelters” ........................................................................................................................................121
5.6 How Do Practicing and Shelter Veterinarians Feel about Pet Sterilization and Potential
Non-Surgical Approaches? ...............................................................................................................123
5.6.1 Private Practice Veterinarians ................................................................................................................123
5.6.2 Shelter Veterinarians .............................................................................................................................124
5.6.3 Key Messages from the Surveys ............................................................................................................124
5.6.4 Other Issues Veterinarians Can Be Expected to Consider ........................................................................125
5.7 Owner Willingness to Pay for a Non-Surgical Alternative..........................................................125
5.8 The “Ideal” Product ..................................................................................................................126
5.8.1 An Initiative to Develop a Single, Permanent, Non-Surgical Sterilant for Male and Female Dogs and Cats ...127
5.9 Commercializing, Manufacturing, and Marketing Products Profitably............................................128
5.10 Marketing Issues in Cats and Dogs: the Bottom Line ...................................................................128
5.10.1 Issues that Affect Marketing of Contraception and Fertility Control for Dogs and Cats ..............................129
6.0 Regulatory Issues: Some Considerations for Evaluating Contraceptives
for Dogs and Cats ......................................................................................................130
6.1 United States Regulatory Agencies ..............................................................................................................130
6.2 European Regulatory Agency .......................................................................................................................131
6.3 Rest of World ..............................................................................................................................................132
6.4 General Considerations and Harmonization Efforts ......................................................................................132
6.5 Time Frame for Regulatory Approval .............................................................................................................132
6.6 Effectiveness ...............................................................................................................................................133
6.7 Target Animal Safety ...................................................................................................................................134
6.8 Human Safety .............................................................................................................................................134
6.9 Environmental Assessment ..........................................................................................................................135
6.10 Manufacturing ..........................................................................................................................................135
6.11 Conclusions ..............................................................................................................................................136
Glossary ............................................................................................................................137
Guide to Acronyms ..........................................................................................................139
Bibliography .....................................................................................................................141
Websites ...........................................................................................................................152
Trademarks and Registered Trademarks ........................................................................154
Contraception and Fertility Control in Dogs and Cats 6
Tables
Table 1-1: Summary of Characteristics Required for Commercialization .................................................................16
Table 3-1: Pros and Cons of Gonadectomy in Dogs and Cats ................................................................................20
Table 3-2: Use of Deslorelin for Contraception in Cats and/or Dogs ......................................................................28
Table 4-1: Entities Profiled in the 2002 Report .....................................................................................................66
Table 4-2: Research Profiled in the 2002 Report ..................................................................................................72
Table 4-3: Universities Involved in Researching Non-Surgical Approaches to Dog and Cat
Contraception/Sterilization. .................................................................................................................75
Table 4-4: Michelson Grants in Reproductive Biology ...........................................................................................81
Table 4-5: Animal Foundation Dog and Cat Over population Projects ....................................................................82
Table 5-1: Overview of US Pet Dog Population .....................................................................................................90
Table 5-2: Overview of US Pet Cat Population ......................................................................................................90
Table 5-3: Miscellaneous Statistics .......................................................................................................................91
Table 5-4: Sources of Pet Dogs and Cats ..............................................................................................................92
Table 5-5: Pet Owner Expenditures ......................................................................................................................93
Table 5-6: Overview of Dog and Cat Ownership in Canada ..................................................................................94
Table 5-7: Age Breakdown of Canadian Dogs ......................................................................................................94
Table 5-8: Annual Estimated Cost of Care (CA$) ..................................................................................................94
Table 5-9: Top 10 European Countries: Dog and Cat Populations 2010 .................................................................95
Table 5-10: Dogs/Person and People/Dog and Cats/Person and People/Cat in the Top 10
European Countries and the US .........................................................................................................96
Table 5-11. Overview of Consumer Expenditure on Pets in Australia in 2009 ........................................................97
Table 5-12: Reasons Japanese Dog Owners Have Dogs (2004) .............................................................................97
Table 5-13: Summary of Reasons Pet Owners Have Not Spayed or Neutered Their Dogs and Cats
in the US (2000 Ralston Purina Study) .............................................................................................101
Table 5-14: Potential Acceptance of a Non-Surgical Alternative to Spay/Neuter ...................................................102
Table 5-15: Reasons Pet Owners Have Had Their Dogs or Cats Spayed or Neutered in the US ..............................103
Table 5-16: Dog Populations in European Countries and Rates of Spay/Neuter ...................................................107
Table 5-17: Examples of Spay/Neuter Costs (Non-Subsidized) .............................................................................108
Table 5-18: Examples of Subsidized or Low-Cost Spay/Neuter Services in the US ................................................109
Table 5-19: Spay/Neuter Costs in Non-US Markets (US$) ....................................................................................111
Table 5-20: Spay/Neuter Costs in the Philippines ................................................................................................111
Table 5-21: Spay/Neuter Costs in Thailand .........................................................................................................112
Table 5-22: Classification of Dogs and Cats by Their Dependence on Humans .....................................................114
Table 5-23: ACC&D Summary of “Key Learnings” ...............................................................................................120
Table 5-24: Issues Affecting Marketing of Contraception and Fertility Control for Dogs and Cats .........................129
Table 6-1: Contraceptive Products Approved by Regulatory Authorities in the US and EU ....................................132
Figures
Figure 5-1: Sources of Pet Dogs and Cats in the US by Percentage .......................................................................93
Figure 5-2: Summary of Reasons Pet Owners Have Not Spayed or Neutered Their Dogs and Cats in the US (%) ...101
Contraception and Fertility Control in Dogs and Cats 7
Dedication
This publication is dedicated to the animals that have inspired us to care so deeply
about this topic, and to a future with new tools to improve the welfare of animals,
especially those animals beyond our grasp today.
Joyce Briggs
President
Alliance for Contraception in Cats & Dogs
Contraception and Fertility Control in Dogs and Cats 8
Preface
In 2002, Katherine Moldave, MBA and Linda been updated by its original author, Linda Rhodes.
Rhodes, VMD, PhD compiled and published Con- ACC&D commissioned this update with the support
traception and Fertility Control in Animals, believed to of a generous grant from PetSmart Charities®. Happi-
be the first effort to summarize the technologies and ly, this has been a more significant undertaking than
issues related to this topic in a comprehensive format originally anticipated since so much has occurred in
that would be useful to scientists, academicians, the the intervening years. ACC&D thanks Ms. Moldave
animal health and welfare industries, and interested for her many hours of work beyond what was con-
laypeople alike. The authors subsequently donated tracted to update and expand the original text; her
the copyright to the Alliance for Contraception in commitment to the project has truly gone above and
Cats & Dogs (ACC&D). beyond.
In the past decade, several contraceptive products Contraception and Fertility Control in Dogs and Cats is
for use in dogs have been approved in various mar- not a scholarly work or exhaustive review article. It is
kets, research in relevant traditional and emerging intended to provide a single source of information and
technologies has expanded greatly, interest in this foster collaboration among interested parties. We are
area of animal health has increased, and, as a key counting on readers to help us identify information
component of our mission, ACC&D has worked to that may not have been included in this compilation
focus stakeholder attention on the opportunities and but should be covered in future updates. We have tried
issues involved in non-surgical approaches to contra- to be as geographically inclusive as possible but ac-
ception and fertility control in “owned” and “un- knowledge that some aspects of the compilation have
owned” cats and dogs. At the end of 2011, ACC&D a United States orientation. Therefore, we are particu-
decided that the time had come to update the por- larly interested in updates, additional information, and
tions of the report related to cats and dogs. perspectives from areas outside the US.
The lead author for Contraception and Fertility Con- The following ACC&D scientific advisors, mem-
trol in Cats and Dogs is one of the original authors of bers of the board of directors, and field experts have
Contraception and Fertility Control in Animals (2002), provided information and/or review and ACC&D is
Katherine Moldave. The regulatory chapter has grateful to them for their invaluable contributions:
�
Cheryl Asa, PhD, Director, AZA Wildlife Contraception Center at the Saint Louis Zoo, St. Louis, MO
�
Joyce Briggs, MS, President, Alliance for Contraception in Cats & Dogs, Portland, OR
�
Scott Coonrod, PhD, Associate Professor, Cornell University College of Veterinary Medicine, Baker Institute,
Laboratory of Epigenetics and Reproductive Biology, Ithaca, NY
�
Karen Green, Senior Director, Alliance for Contraception in Cats & Dogs, Portland, OR
�
Wayne A. Jensen, PhD, MBA, Chief Scientific Officer, Morris Animal Foundation, Denver, CO
�
Wolfgang Jöchle, DVM, DrMedVet, Diplomate ACT, Consultant, semi-retired, Manahawkin, NJ
�
Shirley D. Johnston, DVM, PhD, Director of Scientific Research, Found Animals® Foundation,
Los Angeles, CA
�
Michelle Kutzler, DVM, PhD, DACT, Banfield® Professor of Companion Animal Industries,
College of Agricultural Sciences, Department of Animal Sciences, Oregon State University, Corvallis, OR
�
Julie Levy, DVM, PhD, DACVIM, Director, Maddie’s® Shelter Medicine Program, College of Veterinary Medicine,
University of Florida, Gainesville, FL
�
Elaine Lissner, Medical Director, Parsemus Foundation, San Francisco, CA
�
Patricia N. Olson, Chief Medical Advisor, American Humane Association™, Washington, DC
Contraception and Fertility Control in Dogs and Cats 9
�
Linda Rhodes, VMD, PhD, Chief Scientific Officer, Aratana Therapeutics, Kansas City, KS
�
Margaret Root Kustritz, DVM, PhD, Professor of Small Animal Reproduction, College of
Veterinary Medicine, University of Minnesota, St. Paul, MN
�
Andrew Rowan, PhD, President and CEO, Humane Society International™ and Chief International Officer and Chief
Scientific Officer, The Humane Society of the United States™, Washington, DC
�
Stephen Zawistowski, PhD, CAAB Science Advisor, The American Society for the
Prevention of Cruelty to Animals®, New York, NY
Thanks are also due to our proofreader, Julie Snyder.
This project was supported by a generous grant from
Design donated by MoldaveDesigns LLC. www.moldavedesigns.com.
Disclaimer
This compilation is intended to provide helpful and informative material based upon publicly available information. It is
provided with the understanding that the contributors and ACC&D are not engaged in rendering professional services in
this publication. No liability of any kind is assumed by ACC&D or the contributors with respect to the use of information
contained herein. Although every precaution has been taken in preparation of this publication, ACC&D and the contribu-
tors assume no responsibility for errors or omissions. Neither is any liability assumed for damages resulting from the use
of information contained herein. The publication is not intended as a substitute for the professional advice of a veterinar-
ian in matters relating to animal health and particularly in respect of any products which may require a prescription,
nor is it intended to give specific regulatory advice. All rights are reserved; however, material in this publication may be
reproduced or transmitted provided that ACC&D is notified and credit is given to the Alliance for Contraception in Cats
& Dogs © 2013.

Contraception and Fertility Control in Dogs and Cats 10