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http://veterinarynews.dvm360.com/dvm/Medicine/The-gonad-chronicles-part-1-Neuterings-newestcont/ArticleStandard/Article/detail/829255

Neutering's newest controversy Veterinarians and owners alike are troubled by a new study linking castration and ovariohysterectomy with an increased risk of diseaseincluding some cancers. Should this study change the way we discuss and perform such common, recommended procedures?
Dec 1, 2013 By: Karen L. Overall, MA, VMD, PhD, DACVB, CAAB DVM360 MAGAZIN

This is the first article of a two-part dvm360 series focusing on neutering and the effect of hormones on the development of both physical and behavioral concerns. The following article will explore new research focusing on joint disorders and cancers in both neutered and intact golden retrievers.

All fields, even those governed by scientific principles, are affected by cultural shifts and trends. We see these effects daily in how pet dogs are treated. Dog parks and doggie daycare are modern inventions reflecting both our culture (no one is home for much of the day) and social trends (dog parks offer welcome opportunities for humans to socialize as well). These examples reflect another deeper change in our culture: that dogs are viewed as family members. Many owners believe their pets have social, cognitive and behavioral needs that require special attention. So when a research team from the University of California-Davis (UCD) published a paper earlier this year titled, Neutering dogs: effects on joint disorders and cancers in golden retrievers, 1 its no surprise that both veterinarians and dog owners felt unmoored from one of their cultural tenets that we should neuter dogs for population control and for their health. Listservs and specialists have been inundated with questions about whether we should stop neutering dogs on the basis of this new information. To answer such questions, lets step back, take a deep breath, critically review the data and use it for risk analysis. Designing the study Hormones effect on the development, progression an d treatment outcomes for cancer has been a focus of intense research for decades, but very few populations of any species routinely castrate or perform ovariohysterectomy (OHE) on healthy animals. The exceptional population is dogs in the United States. Most dogs in this country are neutered, in contrast to Scandinavia, where most dogs are intact. arly prepubertal neutering has become more common here over the past 25 years, largely to control the homeless dog population. Additionally, routine veterinary recommendations for dog owners include neutering the pet if there is no intent to breed. These two factors together suggest that American dogs offer a good population for anyone interested in studying the time penetrance of hormonal factors on behavioral and physical health. Accordingly, the authors of the UCD PLOS One paper sought to investigate whether neutering (OHE and castration) created any real increased risk of cancer or other conditions or offered protection from themas had been proposed in a series of papers published mostly within the last two decades. The historical data on hormones and behavioral and physical development suggest that the effects are complex and not always independent of social and physical environments. Hormonal effects on many cancers are also complex. Because hormones affect multiple organ systems, neutering represents an experimental manipulation of all of those systems. The PLOS One study included both male and female dogs and compared those that were intact and those that were neutered. The neutered population was further split into dogs neutered early (< 12 months) and dogs neutered late (>/= 12 months). The authors sought to retrospectively examine the potential effects of neutering on a series of conditions within one breed (in an attempt to control for variation due to breed). They chose a common breed (golden retriever) that has a relatively high incidence of neoplasia. Golden retriever breed clubs also have an active interest in breed health. Because the study was retrospective, the authors sought to further control for differences in populations and diagnosis by using a single hospital database. Uncontrolled variation is a serious problem in epidemiological and risk studies because such variation interferes with interpretation of both statistical and biological effects. The authors examined seven conditions that breeders identified as concerns for golden retrievers: hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HAS), mast cell tumors (MCT), osteosarcoma (OSA) and elbow dysplasia. These conditions have been the subject of other papersnot always with the same conclusionsexamining effects of neutering and hormones (see the references in the PLOS One paper). All of these conditions would be assessed in the context of the three treatment groups: intact, early neutered and late neutered retrievers. Assembling the study group All of the study dogs came from the veterinary teaching hospital database at UCD. Intact and neutered male and female golden retrievers were required to be between 1 and 8 years old, admitted

2 between Jan. 1, 2000 and Dec. 31, 2009 and with the following data in their records: date of birth, date of neutering and date of diagnosis or onset. The authors also collected a body condition score when available. Researchers only included diseases that were present in a minimum of 15 cases (1.5 per year of the study). Furthermore, there had to be evidence linking clinical signs to the disease diagnosis or the dog was not included in the study. Once all of these criteria were met, the sample size for each group was determined (Table 1).

Dogs less than 1 year of age and those 9 years of age and older were not considered for the study, which means that we dont know the outcomes for dogs who were disease-free before the age of 9, but not after. We also have incomplete follow-up for those flagged as affected once they aged out of the study, a finding that limits conclusions about survivorship and potential quality of life. In addition, age of onset may not have been noted or known. Sometimes this information was provided by the referring veterinarian or the owner and not a UCD pathologist. An attempt was made to ensure that age of neutering preceded age of onset for all dogs included in the study, but because of the insidious ways in which many cancers develop and because of the highly variable times of neutering, this goal may not have been met. The authors are completely aware of these limitations and excluded some patients for one disease, but included them for another. The authors further note, A case could be considered as intact for one disease if onset was prior to neutering and considered as late-neutered for another disease that may have occurred after neutering. For all of these reasons, collecting prospective data is preferred for establishing many risks and most mechanisms, but by definition, such studies take a long time. Retrospective studies, on the other hand, are often used to identify associations that may be further investigated in a prospective study, and the PLOS One paper is no exception (for more information, check out the Morris Animal Foundations project on golden retrievers at www.caninelifetimehealth.org/#About/GoldenRetrieverLifetimeStudy). With a retrospective study, you hope that your sample size is large enough that, within the bounds of your specified conditions, you can still say something interesting and potentially helpful. Reviewing the results of the study Early versus late neutered dogs: When comparing early neutered (< 12 months) and late neutered (>/= 12 months) males, there was a statistically significant difference in the number of dogs with CCL and LSA. A greater percentage of early neutered males were diagnosed with these conditions. Two statistical tests with slightly different assumptions were used for each analysis. Only one of these tests produced a statistically significant effect with respect to HD and more early neutered males were diagnosed with this condition. For females, there was a statistically significant difference only for those affected with CCL, reflecting a greater percentage among early neutered dogs.

Early neutered versus intact dogs: When comparing early neutered with intact male dogs, there was a statistically significant difference in the number of dogs diagnosed with HD, CCL and LSA. A greater percentage of neutered males was diagnosed with these conditions. For females, there was a statistically significant difference only for CCL, with more early neutered dogs being diagnosed. Late neutered versus intact dogs: There was no statistically significant effect for any of these conditions when late neutered dogs were compared with intact dogs. Using this data, we can now identify specific patterns of concern by comparing the numbers in each group. However, we cannot establish risk in a true statistical sense because of the datas limitations. (The relevant data can be found in Tables 2 and 3.)

So what can we say? In this sample of golden retrievers, between the ages of 1 and 8, inclusive, and admitted to the veterinary teaching hospital at UCD over a decade of study, the number of male dogs with HD who were early neutered (N=16) was twice that of dogs who were intact (N=17). In early neutered dogs of both sexes, the early neutered dogs (N=9 for males and N=13 for females) were more likely to have CCL than either intact (N=0 for males and N=0 for females) or late neutered dogs (N=1 for males and N=0 for females). Early neutered males (N=17) had three times the occurrence of LSA compared with intact males (N=5), for the 22 total male dogs diagnosed over the decade of the study. So what can we say? In this sample of golden retrievers, between the ages of 1 and 8, inclusive, and admitted to the veterinary teaching hospital at UCD over a decade of study, the number of male dogs with HD who were early neutered (N=16) was twice that of dogs who were intact (N=17). In early neutered dogs of both sexes, the early neutered dogs (N=9 for males and N=13 for females) were more likely to have CCL than either intact (N=0 for males and N=0 for females) or late neutered dogs (N=1 for males and N=0 for females). Early neutered males (N=17) had three times the occurrence of LSA compared with intact males (N=5), for the 22 total male dogs diagnosed over the decade of the study. Putting the research into practice The authors note that they cannot extend their results to other breeds, or even to dogs, in general. Imagine if all of the dogs that had no disease at the age of 8 developed it at the age of 10 and dropped dead? The analysis would look vastly different. We know cancer is a time-penetrant condition, and early cancers, especially those of pre-reproductive age, are rare in any species. Any causal attribution for neutering and neoplasia and other non-behavioral pathologies is also premature. But we may be able to use breed to identify when there may be an increased genetic risk and hence a putative mechanismfor any type of disease. The PLOS One study did not consider that some of the dogs in their study could be members of overlapping family lines and hence not independent cases. The study also did not address another type of breed canalization that associated with work. Dogs that are bred for conformation versus work, whether the work is as a military working dog, a herding dog or a field trial dog, are different both behaviorally and genetically. In turn, these groups may produce

4 different outcomes for such studies. Given these state-of-the-art data, we can conclude that there is no one recommendation that will fit each client and each dog. If the dog is a shelter or rescue animal, neuter the dog immediately if its healthy enough to undergo the procedure. The risk hereespecially in a country like the United States where unwanted, neglected dogs number in the millionsis that we must decrease the population entering shelters. And, although puppies are considered more adoptable, we must decrease the number of pups coming in from the street or being born into shelters. Too many of these young animals may have epigenetic effects from poor maternal and grandmaternal experiences, and too many of them have poor early or in utero nutrition.2 This is a formula for creating pathological reactivity, and I see a nonstop stream of these dogs in my patient population, in shelters and rescues, and through those who e-mail me for help. The Scandinavians do not seem to have the same unwanted dog population that we do, so they make different decisions. But we must intervene in this tragic situation. Note: In the second part of this series, we will review data outlining neutering and hormonal effects on behavior and look at some more information about hormones and neoplasia. References: 1. De la Riva GT, Hart BL, Farver TB, Oberbauer AM, Messam LL, Willits N, Hart LA. Neutering dogs: effects on joint disorders and cancers in golden retrievers. PLOS One 2013;8(2):e55937. 2. Overall KL. Editorial: Caring for the brains of young pups. Vet Rec2011;169(18):465-466.
http://veterinarynews.dvm360.com/dvm/Medical+news/The-gonad-chronicles-part-2-Veterinaryresearch-ex/ArticleStandard/Article/detail/831269?contextCategoryId=45677 This is the second article of a two-part dvm360 series focusing on neutering and the effect of hormones on the development of both physical and behavioral concerns. We will explore the relevant data demystifying the connection between hormones, behavior and health.

Much attention has been given to the role of sex hormones and behavioral concerns in cats and dogs, but there is surprisingly little data on the subject. The most common stereotypes involve testosterone in intact males. It may be appropriate to view testosterone as a behavioral modulator that could help bring about or escalate the aggressive state. 1An intact dog may react more easily, escalate any response more quickly, plateau at a higher level of reactivity, return to baseline at a slower rate and possibly alter his baseline to a higher level than would a neutered dog. That said, both neutered and intact dogs may exhibit behavioral concerns, and only some of these concerns are affected by sexual dimorphism. Dimorphic behaviors associated with the presence of testosterone include urine marking with lifted leg, roaming and some types of mounting. Mounting is an unclear issue because it occurs in a number of contexts, most of which are not sexual, and both sexes do it. Castration results in an androgen drop within six hours, and most hormones that decrease do so within 72 hours.2 In the 1976 Hopkins study, which looked at male behavioral patterns and the effect of castration, roaming decreased by approximapattely 90 percent, male-to-male aggression by approximately 75 percent, urine marking by approximately 60 percent and mounting by 80 percent in male dogs that were neutered. However, marking, mounting and fighting are complex behaviors not wholly controlled by hormones. There is a significant learning component involved in practicing these behaviors that won't be redressed by castration. Context also matters, so space and social interactions need to be considered. Finally, no distinction is made between normal and pathological behaviors, and one might expect castration to affect them differently. Researchers have paid less attention to the role of female sex hormones and aggressive behavior, but one study has made a connection within a fairly restricted population.3 Only female puppies that were already showing signs of "dominance aggression" became worse after spaying. Spaying had no effect on any other age and behavior group combinations.4 It is possible that for these young, aggressive bitches, sex hormones play a helpful role in modulating their reactivity. If these dogs are in responsible households where breeding is prohibited, allowing them to have a heat cycle may be beneficial in terms of ameliorating their aggression, but there is little data on this. Reasons for neutering Neutering (castration or ovariohysterectomy) is usually recommended for aggressive dogs and cats, not because it is therapeutic but because it prevents a heritable behavior component from being passed on. If heritability is complex or has a large environmental component to expression, neutering dogs known to be aggressive may not substantially decrease genetic risk within the population of breeding dogs as much as we would like. Owners may choose to neuter their dog for many different reasons, which can vary by sex. Common reasons for neutering male dogs include: the dog marks with urine, the dog has an enlarged prostate, the dog has prostatic or testicular neoplasia, or the working dog is more focused on other dogs' odors than on his job. Common reasons for neutering females include a desire to decrease the risks of mammary neoplasia to the fullest extent possible. In some cases, the client cannot or will not monitor for pyometra or doesn't want to deal with the behavioral and physical consequences of heat cycles.

5 The most common reason for ovariohysterectomy (OHE) is to spare dogs the risk of mammary neoplasia, which is extremely common in dogs, but only malignant about half the time. 5 In countries where dogs are not routinely spayed, the risk for mammary neoplasia may be as high as 53 percent.6 Neutering female dogs before their first heat appears to decrease the risk of mammary neoplasia to 0.5 percent. If clients wait until the second heat, the risk is 8 percent, and after the second heat, the risk increases to 26 percent. 7 While spaying after the second heat does not reduce risk, spaying at the time the mammary tumors are removed appears to have a beneficial effect on survival. 8,9 Some authors don't feel that the data is strong enough to say there is any mammary sparing effect because of problems with bias in the data.10 The patterns for OHE and mammary neoplasia are similar in cats, but 85 to 90 percent of feline mammary tumors are malignant.5,11 Repeated heat cycles increase the risk of pyometra. 12 In one study, by 10 years of age, 25 percent of the females studied developed pyometra. There are strong breed attributes that may increase or decrease this risk, but OHE eliminates this risk altogether. 13 The risk of prostatic disease in male dogs increases with age. Benign hypertrophy may affect at least 60 percent of dogs older than 7 years. 14 Castration both prevents and treats benign prostatic hyperplasia. Testicular tumors are fairly rare and most are prevented or treated by castration. However, most prostate cancer, when diagnosed, is advanced and does not respond to androgen deprivation, so monitoring is important for a favorable outcome.15 Other health issues Additional studies have raised concerns about neutering's adverse effects on other health issues. Castration may increase the risk of bladder transitional cell carcinoma 16 and prostate carcinoma,16,17 an effect augmented by breed. At least one study suggests that neutering may facilitate tumor growth while having no effect on initiating cancer development.18 Neutered dogs have been reported to have a high risk for osteosarcoma compared with intact dogs,19,20 but the studies are complicated by other factors and the neutered dogs actually lived longer than the intact dogs. Spayed females have been reported to have an increased risk of hemangiosarcoma, when compared with intact females,21,22 a finding that may be heavily influenced by breed, but not supported by the PLoS One study that stimulated this debate.23 Transitional cell carcinoma may affect more neutered than intact females, but it is rare, although more common in females.24 Early neutering, as practiced on shelter dogs to reduce the number of unwanted animals, may have different effects on health than neutering later in life. Early neutering increases long bone growth, which may pose risks for later skeletal conformations, potentially affecting hip dysplasia, 25-28 but these findings are not supported by all studies,29 and even when present, the effect may be relatively weak.28 If OHE for female shelter puppies can be delayed until 3 months of age, risks for temporal, related cystitis and later urinary incontinence may be decreased,28 but this may matter less than anticipated.29 If the risk is that the pup would not otherwise be neutered, neutering of shelter dogs is always preferred. One retrospective case series evaluating the true prevalence of urinary incontinence in spayed female dogs that were neutered across ages produced two findings: acquired urinary incontinence had a low prevalence (N=29 or 5.12 percent in 566 dogs), and there was no effect of age at OHE between the continent and incontinent dogs.30 Chemical castration with implantable deslorelin, a gonadotropin-releasing hormone (GnRH) agonist, is occasionally used because it renders animals functionally sterile, a condition that is reversible with removal of the implant.31 Deslorelin decreases testosterone and luteinizing hormones to undetectable levels in dogs and so may also affect testosterone-modulated behaviors. When alpha-agonists fail, deslorelin may successfully treat estrogen-dependent urinary incontinence in female dogs.32 In ferrets, those treated with deslorelin showed decreased fighting associated with sexual behavior and increased play behavior when compared with ferrets who had been surgically castrated. 33 One study that examined play, fear and aggressive behaviors in dogs treated with deslorelin compared with those surgically castrated found no differences between groups. 34 When given to cats, deslorelin rendered them infertile, caused decreases in testicular volume and disappearance of penile spines.35 Cats that were implanted experienced decreased libido, decreases in mounting and mating behaviors, and decreased spraying, but food intake increased, a potential concern given the obesity epidemic in cats. Recommendations Any causal attribution for neutering and problematic behavior is premature, although I have not touched on hormones and brain agingan even more complex issue. Frankly, behavioral studies are much harder to do than studies focusing purely on somatic conditions. When one considers the difficulty of identifying physical pathologies that may be affected by neutering, one should take special care with behavioral evaluations, which are much more difficult to evaluate in an unbiased, valid and repeatable manner.

6 So what do I recommend to owners seeking guidance? If the dog has any pathology that might be heritablebehavioral or otherwisethe dog should not be bred unless the breeding is part of a funded, approved, controlled study in collaboration with researchers to study the putative defect. Neutering is not the only way of preventing breeding but it is the easiest. If the dog has no behavioral concerns and the owners are responsible, discuss all of the health information outlined above. While the Hopkins study has never been replicated or expanded, I still note to clients that dogs that are searching for mates are a lot like college students in bars: They are not typically thinking about the consequences of their behavioral choices. Too often these dogs roam and are killed by cars. Clients keeping intact males must be mindful of keeping them safe. In summary, we need to learn more about patterns of all pathologies in all breeds so we can help produce physically and behaviorally healthier animals that are excellent at their jobs whether they're bred to be excellent pets or to be service, working, trial or hunting dogs and that will always have caring, humane homes. Neutering naysayers One study has suggested that neutered dogs are more fearful, excitable, aggressive and less trainable than are intact dogs.36 Unfortunately, this study is flawed in that it does not follow dogs through time and instead relies on unmatched cohorts. We do not know whether these dogs were all evaluated at the same age (a control for ontogeny) or at a predetermined time after neutering (a control for postoperative effects). Without these controls, most correlations especially using scored and ranked data, as is the case hereare likely to be spurious. There are other major methodological issues that preclude accepting these conclusions as valid and they are common enough mistakes in studies to warrant an outline here. > The data are scored clients' assessments of their dog's behaviors using a scale that was not validated to ensure it represented reliable, repeatable behaviors ( e.g., whether the dog was actually "aggressive" if she barked). > No inter-rater reliability data are provided. In other words, we have no idea how variable clients' interpretations of the dogs' behaviors were or how variable their interpretation of the terms and scales were. > Scaled data are difficult to interpret because they are so subjective and without inter- and intrarater reliabilities, it is impossible to know, for example, if person A's 4.5 is equivalent to person B's 4.5. This is one reason why such scales should be avoided in population studies unless they are defined, validated and tested for inter-rater agreement (e.g., Kappa scores). > The data are presented graphically and the axes are not the same. As a result, differences appear larger than they truly are. When plotted on the same scale, differences are modest, especially given that very small changes in scores obtained from scaled responses are calculated for a very large number of responses. > The sample size is huge, because this is a survey study, and with a sample size so large it would be odd if some findings were not significant, by chance alone. This effect is magnified when scores are calculated from scales. Even for those relationships that are statistically different, we have no idea if the differences noted are biologically meaningful. > Analysis of ratios is complex (in this case, bone length), and requires certain assumptions which we cannot know were met here. REFERENCES 1. Eiseneger C, Haushofer J, Fehr E. The role of testosterone in social interaction. Trends Cogn Sci 2011;15(6):263-271. 2. Hopkins SG, Schubert TA, Hart BL. Castration of adult male dogs: effects on roaming, aggression, urine marking, and mounting. J Am Vet Med Assoc1976;168(12):1108-1110. 3. OFarrell, V, Peachey, E. Behavioural effects of ovariohysterectomy on bitches. J Small Anim Pract 1990;31(12):595-598. 4. Overall KL. Sex and aggression. Canine Practice 1995;20(3):16-18. 5. Brodey RS, Goldschmidt MA, Rozel JR. Canine mammary gland neoplasm. J Am Anim Hosp Assoc 1983;19:61-90. 6. Moe L. Population-based incidence of mammary tumours in some dog breeds. J Reprod Fertil Suppl 2001;57:439-443. 7. Schneider R, Dorn CR, Taylor DO. Factors influencing canine mammary cancer development and postsurgical survival. J Natl Cancer Inst 1969;43(6):1249-1261. 8. Sorenmo KU, Shofer FS, Goldschmidt MH. Effect of spaying and timing of spaying on survival of dogs with mammary carcinoma. J Vet Intern Med2000;14(3):266-270. 9. Overley B, Shofer FS, Goldschmidt MH, et al. Association between ovariohysterectomy and feline mammary carcinoma. J Vet Intern Med2005;19(4):560-563. 10. Beauvais W, Cardwell, JM, Brodbelt DC. The effect of neutering on the risk of mammary tumours in dogsa systematic review. J Small Anim Pract2012;53(6):314-322.

7 11. Lana SE, Rutteman GR, Winthrow SJ. Tumors of the mammary gland. In: Withrow and MacEwen's small animal clinical oncology. 4th ed. St. Louis, Mo: Elsevier, 2007;619-636. 12. Johnston SD, Root Kustritz MV, Olson PS. Canine and feline theriogenology. Philadelphia, Pa: WB Saunders Co, 2001:80-87. 13. Egenvall A, Hagman R, Bonnett BN, et al. Breed risk of pyometra in insured dogs in Sweden. J Vet Intern Med 2001;15(6):530-538. 14. Berry SJ, Coffey DS, Strandberg JD, et al. Effect of age, castration, and testosterone replacement on the development and restoration of canine benign prostatic hyperplasia. Prostate 1986;9(3):295-302. 15. Leroy BE, Northup N. Prostate cancer in dogs: comparative and clinical aspects. Vet J 2009; 180(2):149-162. 16. Bryan JN, Keeler MR, Henry CJ, et al. A population study of neutering status as a risk factor for canine prostate cancer. Prostate 2007;67(11):1174-1181. 17. Sorenmo KU, Goldschmidt M, Shofer F, et al. Immunohistochemical characterization of canine prostatic carcinoma and correlation with castration status and castration time. Vet Comp Oncol 2003;1(1):48-56. 18. Teske E, Naan EC, van Dijk EM, et al. Canine prostate carcinoma: epidemiological evidence of an increased risk in castrated dogs. Mol Cell Endocrinol2002;197(1-2):251-255. 19. Ru G, Terracini B, Glickman LT. Host related risk factors for canine osteosarcoma. Vet J 1998;156(1):31-39. 20. Cooley DM, Beranek BC, Schlittler DL, et al. Endogenous gonadal hormone exposure and bone sarcoma risk. Cancer Epidemiol Biomarkers Prev2002;11(11):1434-1440. 21. Prymak C, McKee LJ, Goldschmidt MH, et al. Epidemiologic, clinical, pathologic, and prognostic characteristics of splenic hemangiosarcoma and splenic hematoma in dogs: 217 cases (1985). J Am Vet Med Assoc 1988;193(6):706-712. 22. Ware WA, Hopper DL. Cardiac tumors in dogs: 1982-1995. J Vet Intern Med1999;13(2):95103. 23. Torres de la Riva G, Hart BL, Farver TB, et al. Neutering dogs: effects on joint disorders and cancers in golden retrievers. PLoS One 2013;8(2):e55937. 24. Norris AM, Laing EJ, Valli VE, et al. Canine bladder and urethral tumors: a retrospective of 115 cases (1980-1985). J Vet Intern Med 1992;6(3):145-153. 25. Salmeri KR, Bloomberg MS, Scruggs SL, et al. Gonadectomy in immature dogs: effects on skeletal, physical, and behavioral development. J Am Vet Med Assoc1991;198(7):1193-1203. 26. Salman MD, New JG Jr., Scarlett JM, et al. Human and animal factors related to relinquishment of dogs and cats in 12 selected animal shelters in the United States. J Appl Anim Welf Sci 1998;1(3):207226. 27. Salman MD, Hutchison J, Ruch-Gallie R, et al. Behavioral reasons for relinquishment of dogs and cats to 12 shelters. J Appl Anim Welf Sci2000;3(2):93-106. 28. Spain CV, Scarlett JM, Houpt KA. Long-term risks and benefits of early-age gonadectomy in dogs. J Am Vet Med Assoc 2004;224(3):380-387. 29. Howe LM, Slater MR, Boothe HW, et al. Long-term outcome of gonadectomy performed at an early age or traditional age in dogs. J Am Vet Med Assoc2001;218(2):217-221. 30. Forsee KM, Davis GJ, Mouat EE, et al. Evaluation of the prevalence of urinary incontinence in spayed female dogs: 566 cases (2003-2008). J Am Vet Med Assoc2013;242(7):959-962. 31. Junaidi A, Williamson PE, Cummins JM, et al. Use of a new drug delivery formulation of the gonadotrophin-releasing hormone analogue Deslorelin for reversible long-term contraception in dogs. Reprod Fertil Dev 2003;15(6):317-322. 32. Reichler IM, Hubler M, Jchle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. Theriogenology2003;60(7):1207-1216. 33. Vinke CM, van Deijk R, Houx BB, et al. The effects of surgical and chemical castration on intermale aggression, sexual behaviour and play behaviour in the male ferret (Mustela putorius furo). Appl Anim Behav Sci 2008;115(1-2):104-121. 34. Steur ER. Chemical and surgical castration of male dogs: behavioral effects . Doctoral thesis, University of Utrecht, Utrecht, Holland, 2011. 35. Goericke-Pesch S, Georgiev P, Antonov A, et al. Clinical efficacy of a GnRH-agonist implant containing 4.7 mg deslorelin, Suprelorin, regarding suppression of reproductive function in tomcats. Theriogenology 2011;75(5):803-810. 36. Farhoody P, Zink MC. Behavioral and physical effects of spaying and neutering domestic dogs (Canis familiaris). Unpublished summary of a Masters thesis, Hunter College, New York, NY, 2010. Dr. Karen L. Overall is a researcher, editor of The Journal of Veterinary Behavior: Clinical Applications and Research, and author of more than 100 publications, dozens of chapters and a new book, The Manual of Clinical Behavioral Medicine for Dogs and Cats .