Session I

Session I: Non-reproductive Effects of Spaying and Neutering
SESSION OVERVIEW Dr. John Verstegen

Session presenters were Dr. John Verstegen, Dr. Deborah Duffy, Dr. Karine VerstegenOnclin, Dr. Iris Reichler and Dr. Vic Spain (see separate documents for individual presenters materials). Although the total number of dogs and cats humanely killed annually in the United States has decreased significantly over the last 20 years, the numbers are still in the millions. Accurate national shelter data does not exist, but estimates suggest that between 5 and 11 million (possibly even more) dogs and cats are handled annually by approximately 5,000 shelters. Around 50% are euthanized, 15% are reclaimed by their owners, and the rest are adopted. Spay and neuter is widely accepted as the solution to pet overpopulation and population control. In veterinary colleges with shelter medicine specialties, spay/neuter is presented as the contraceptive technique of choice. In many veterinary colleges, this is often the only contraceptive approach taught to veterinary students. Surgical sterilization indeed has some clear advantages: It is irreversible, is relatively easy to perform, is well introduced across the country, and is generally accepted. However, the technique also has some limitations: Surgical sterilization can be expensive; there are risks of surgery and anesthesia; there can be side effects and pain; the procedure requires an infrastructure and specialized knowledge; and it is not appropriate in all situations. Further, although spay/neuter has been widely used for more than 20 years, the generally marvelous reproductive efficiency of cats and dogs has been such that the homeless pet problem remains an acute societal, individual and ethical problem. The ideal contraceptive approach (as stated by Brown and Moskovitz years ago, and taken from Berelson in 1964) should be long-acting or irreversible, highly effective, and safe; it should produce few or no side effects; it should require limited or no need for significant action to be applied; and it should necessitate no continuing supplies and be low cost. The objectives of the first session were to look closely at surgical sterilization in this context. Does spay/neuter meet these requirements noted above? It is important to understand the gold standard in order to have a benchmark against which non-surgical approaches can be compared. Dr. Duffy presented results from a large epidemiological study that called into question generally held beliefs about the effects of spaying on dogs behavior. The results of that study suggested that spayed female dogs of some breeds tend to be more aggressive
Proceedings of the Third International Symposium on Non-Surgical Contraceptive Methods for Pet Population Control www.acc-d.org
Session I: Non-reproductive Effects of Spaying and Neutering toward humans than intact females. The effects of castration on behavior, particularly aggressive behavior, were clearly questioned, indicating a need for further studies. Dr. Verstegen-Onclin presented preliminary data concerning the possible relation between early spaying and abnormal external genital development leading to chronic vestibule-vaginal infection and UTI. Since early-age spaying is a relatively recent approach to population control in carnivores, long-term data are unavailable and recent data are now slowly accumulating, allowing detection of side effects not observed or not taken into consideration in the previously published studies. Even if preliminary, these observations present new questions and deserve further investigation. Dr. Reichler summarized the results accumulated over 10 years in her laboratory showing the relation between spaying and urinary incontinence, a common side effect with poorly understood pathogeny in the spayed dog. Directly or indirectly, through GnRH and the gonadotrophins, acting at the periphery or centrally, the reproductive axis seems to be involved in the regulation of continence. Dr. Spain, who has been recently involved in many studies assessing the long-term risks and benefits of early-age neutering, presented convincing data about the effects of spay/neuter on hip dysplasia, cranial cruciate ligament rupture, long bone development, body weight, diabetes, urinary tract infections, mammary cancer, and several other conditions. Like the preliminary study of Dr Verstegen-Onclin, Dr. Spain advises delaying sterilization of females until after four months of age. The main interest of this session was to take an objective and careful look at the nonreproductive effects of spay/neuter. Looking for alternatives, we have been too often caught up by insisting on an ideal drug or technique that would be without side effects, bias or pitfalls. In reality, there is not likely to be one magic treatment that can instantly, inexpensively and permanently sterilize a male or female cat or dog with no risk of undesired effects. At this stage, spay/neuter still remains the only acceptable standard to control population in dogs and cats, but this gold standard is probably not as efficacious, safe or devoid of side effects as generally considered. The presence of unwanted side effects or problems related to surgical spay/neuter allows us to compare the value of this reference and to consider the development of new alternatives with more realism.
PRESENTATION SUMMARY & POWERPOINT Non-reproductive Effects of Spaying and Neutering on Behavior in Dogs
Deborah L. Duffy, Ph.D., and James A. Serpell, Ph.D., Center for the Interaction of Animals and Society, School of Veterinary Medicine, University of Pennsylvania Although there are scattered reports in the literature of apparently adverse effects of spaying and neutering on canine behavior, there are very few quantitative studies and most of these have employed behavioral measures of unknown reliability and validity. The present study used the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) to investigate the impact of spaying/neutering in various dog populations, including (1) a random sample of 1,552 dogs belonging to 11 common breeds and (2) a convenience sample of over 6,000 dogs of various breeds recruited via an online survey. The C-BARQ is a reliable, standardized method for evaluating and screening dogs for the presence and severity of behavioral problems. It was developed by behavioral researchers at the University of Pennsylvania (Hsu and Serpell, 2003) and consists of a 101-item questionnaire that is simple to use, takes about 15 minutes to fill out, and can be completed by anyone who is reasonably familiar with the dogs typical responses to ordinary, day-to-day events and stimuli. The C-BARQ is currently the only existing behavioral assessment instrument of its kind to be thoroughly tested for reliability and validity on large samples of dogs of various breeds. This process has resulted in the identification of the following 13 distinct behavioral factors or traits that are common to the majority of dogs, regardless of breed, age, sex or neuter status: 1. Stranger-directed aggression: Dog shows threatening or aggressive responses to strangers approaching or invading the dogs or the owners personal space, territory, or home range. 2. Owner-directed aggression: Dog shows threatening or aggressive responses to the owner or other members of the household when challenged, manhandled, stared at, stepped over, or when approached while in possession of food or objects. 3. Dog-directed fear/aggression: Dog shows fearful and/or aggressive responses when approached directly by unfamiliar dogs. 4. Familiar dog aggression: Threatening or aggressive responses during competition for resources with other (familiar) dog(s) in the household. 5. Stranger-directed fear: Fearful or wary responses when approached directly by strangers.
Session I: Non-reproductive Effects of Spaying and Neutering 6. Nonsocial fear: Fearful or wary responses to sudden or loud noises, traffic, and unfamiliar objects and situations. 7. Separation-related behavior: Vocalizes and/or engages in destructive behavior when separated from the owner, often accompanied or preceded by behavioral and autonomic signs of anxiety, including restlessness, loss of appetite, trembling, and excessive salivation.
8. Attachment and attention-seeking: Maintains close proximity to the owner or other members of the household, solicits affection or attention, and becomes agitated when the owner gives attention to third parties. 9. Trainability: Shows willingness to attend to the owner, obeys simple commands, fetches objects, responds positively to correction, and ignores distracting stimuli. 10. Chasing: Pursues cats, birds, and other small animals, given the opportunity. 11. Excitability: Strong reaction to potentially exciting or arousing events, such as going for walks or car trips, doorbells, arrival of visitors, and the owner arriving home; difficulty settling down after such events. 12. Touch sensitivity: Fearful or wary responses to potentially painful procedures, including bathing, grooming, claw-clipping, and veterinary examinations. 13. Energy level: Highly energetic, boisterous, and/or playful behavior. The results of the study suggest that spayed female dogs tend to be more aggressive toward their owners and to strangers than intact females, but that these effects of spaying on behavior appear to be highly breed-specific. Contrary to popular belief, the study found little evidence that castration was an effective treatment for aggressive behavior in male dogs, and may exacerbate other behavioral problems. Further research will be needed to clarify the relationship between age of spaying/neutering and these apparent effects on behavior.
Reference
Hsu, Y., and Serpell, J.A. 2003. Development and validation of a questionnaire for measuring behavior and temperament traits in pet dogs. J. Amer. Vet. Med. Assoc., 223: 1293-1300.
Session I: Non-reproductive Effects of Spaying and Neutering Effects on Behavior By Dr. Deborah Duffy
BEHAVIORAL EFFECTS OF SPAYING/NEUTERING IN DOMESTIC DOGS

Deborah L. Duffy, Ph.D. James A. Serpell, Ph.D.
Center for the Interaction of Animals & Society School of Veterinary Medicine University of Pennsylvania
OFTEN CITED BEHAVIORAL REASONS TO SPAY/NEUTER A PET:

(from websites of veterinary clinics, humane societies, trainers & animal shelters)
Spaying and neutering makes pets better, more affectionate companions. Female dogs, like males, have an increased risk of aggression if left intact.
Unsterilized animals often exhibit more behavior and temperament problems than do those who have been spayed or neutered.
It is true that unneutered dogs are often more aggressive and territorial (urine marking, fighting), but these traits should not be confused with loyalty and protection of their home and family.
The only behavior changes that are observed after neutering relate to behaviors influenced by male hormones.
..any (behavioral) change would be for the better. Altered pets are less aggressive toward other dogs and cats, are less likely to urine mark and wander, and generally have better personalities.
QUESTIONS:
What effects does spaying/neutering have on nonreproductive behaviors? Sex differences? Breed differences?
Canine Behavioral Assessment & Research Questionnaire (C-BARQ)

http://www.vet.upenn.edu/cbarq/
101 Questions: 5-point scale mixture of severity scales and frequency scales
The C-BARQ Factors or Traits

Stranger-directed aggression (10 items) Owner-directed aggression (8 items) Dog-directed fear/aggression (8 items) Dog rivalry (4 items) Stranger-directed fear (4 items) Nonsocial fear (6 items) Separation-related behavior (8 items) Attachment/attention-seeking (6 items) Trainability (8 items) Chasing (4 items) Excitability (6 items) Touch sensitivity (4 items) Energy (2 items)
Miscellaneous C-BARQ Items
Item 78: Escaping/roaming Item 79: Rolling in scent Item 80: Coprophagia (eating feces) Item 81: Chewing objects Item 82: Mounting Item 83: Food begging Item 84: Food stealing Item 85: Fear of stairs Item 86: Pulling on leash Item 87: Marking with urine Item 88: Submissive/emotional urination
Item 89: Separation urination Item 90: Separation defecation Item 91: Hyperactivity Item 94: Staring (obsessive) Item 95: Snapping at flies (obsessive) Item 96: Tail-chasing Item 97: Shadow/light-chasing Item 98: Barking Item 99: Autogrooming (self) Item 100: Allogrooming (others) Item 101: Other abnormal/stereotypic
Random Sample Survey

Respondents: 1,552 dog owners (breed club members) Dogs Age: ! 1 year old (mean 6 years, Std.dev. 3.2 yrs) Sex: Male:Female ratio = 1:1 40% Spayed/Neutered
Basset Hounds
Dachshunds
English Springer Spaniels
West Highland White Terriers
Yorkshire Terriers
n = 152
n = 122
n = 254
n = 93
n = 93
Golden Retrievers
Labrador Retrievers
Poodles
Shetland Rottweilers Sheepdogs
Siberian Huskies
n = 179
n = 281
n = 71
n = 94
n = 117
n = 96
Reasons for Spaying/Neutering:
Birth Control Required by Shelter/Breeder Control/Prevent Behavior Problems Control/Prevent Health Problems Recommended by Veterinarian Other
Percent 41.8 2.2 18.1 31.4 .5 6.0
SPAYED FEMALES ARE MORE AGGRESSIVE TOWARD PEOPLE
** *
** p < 0.025
* p = 0.06 Mann-Whitney U test
SPAYED FEMALES ARE MORE FEARFUL AND SENSITIVE TO TOUCH
**
* p < 0.05
** p < 0.025 Mann-Whitney U test
NEUTERED MALES MARK THEIR TERRITORIES LESS OFTEN TERRITORIES
n = 502
n = 80
* p < 0.005
Mann-Whitney U test
SPAYED/NEUTERED DOGS BEG FOR FOOD AND LICK PEOPLE/OBJECTS MORE OFTEN
**
**
n=398 n=188
n=502 n=79
n=406 n=189
n=520 n=80
INTACT SPAYED/NEUTERED
** p < 0.001 * p < 0.004 Mann-Whitney U test
BREED-SPECIFIC EFFECTS OF SPAYING/NEUTERING DOG-DIRECTED AGGRESSION/FEAR

*** * **
*** p < 0.005 (dog-directed aggression/fear) * p < 0.05 (dog-directed fear) ** p < 0.05 (dog-directed aggression)
Convenience Sample Survey

Respondents: 3,593 dog owners (open-access to C-BARQ website) Only 1 dog per owner Dogs: Age: 6 months 23 years (mean 4.8 years, Std.dev. 3.2 yrs) Sex: Male:Female ratio = 1:1 76% Spayed/Neutered 17 breeds (plus mixed breeds) with sample size of > 50 dogs each Reasons for spaying/neutering: Birth control (40%) Required by breeder/shelter (30%)
SPAYED/NEUTERED DOGS ARE MORE AGGRESSIVE TOWARD PEOPLE AND OTHER DOGS
**
**
**
n=247 n=672
n=276 n=542
n=283 n=766
n=353 n=638
** p < 0.0001 * p < 0.0005

Bonferroni corrected p value: 0.0016
Mann-Whitney U test
SPAYED/NEUTERED DOGS ARE MORE FEARFUL AND SENSITIVE TO HANDLING
n=277 n=716
n=351 n=597
n=267 n=709
n=328 n=603
* p < 0.0001 Mann-Whitney U test
SPAYED DOGS ARE LESS ENERGETIC
*
Mean (+/- 95% confidence intervals)
n=297 n=818
n=374 n=696
SPAYED/NEUTERED DOGS ROLL IN & EAT FECES MORE OFTEN
* * *
n=282 n=794
n=351 n=662
n=294 n=803
n=366 n=680
10
NEUTERED DOGS BEG & STEAL FOOD MORE OFTEN
* *
n=294 n=817
n=368 n=693
n=294 n=814
n=364 n=691
SPAYED/NEUTERED DOGS SELF-GROOM & BARK EXCESSIVELY
Mean (+/- 95% confidence intervals)
**
**
n=298 n=817
n=372 n=696
n=298 n=818
n=373 n=695
** p < 0.0001 * p < 0.001 Mann-Whitney U test
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BREED-SPECIFIC EFFECTS OF SPAYING/NEUTERING TOUCH SENSITIVITY
ns
ns
n=23 n=51
n=37n=28
n=39 n=31
n=40 n=24
n=21 n=85
n=26 n=55
FEMALE
MALE
FEMALE
MALE
FEMALE
MALE
* p < 0.002
Mann-Whitney U test
SEX-SPECIFIC EFFECTS OF SPAYING/NEUTERING
**
n=22
n=28
n=28
n=13
* p < 0.025 ** p < 0.01 Mann-Whitney U test
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SUMMARY
For most behaviors, spaying/neutering was associated with worse behavior, contrary to conventional wisdom. A few behaviors (e.g., energy level, urine marking) were reduced in spayed/neutered dogs. The effects of spaying/neutering are often specific to certain breeds and are not always equivalent between sexes.
CONCLUSIONS
Significant differences in scores do not necessarily indicate severe behavioral problems. Neutering male dogs does not render them useless for protection or guarding. We need to investigate mechanisms for behavioral effects of spaying and develop alternatives. Dog owners need to receive accurate information to help them form realistic expectations.
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ACKNOWLEDGEMENTS
Dr. Yuying Hsu (Nat. Taiwan Normal University). Kathy Kruger (Univ. of Pennsylvania). The Arell Foundation, The Kenneth A. Scott Charitable Trust, The Pet Care Trust, The University of Pennsylvania Research Foundation, AKC Canine Health Foundation, and the Arthur L. Bud Johnson Foundation. Various breed clubs. All participants.
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Session I: Non-reproductive Effects of Spaying and Neutering Effects on the Urogenital System By Dr. Karine Verstegen-Onclin
Surgical neutering and the external reproductive system in the dog

Karine Verstegen-Onclin, DVM, PhD, DECAR John Verstegen, DVM, PhD, MSc, DECAR University of Florida, Gainesville
Embryology of the female reproductive tract development

Fusion of the paramesonephric (Mullerian) ducts to form uterine body, cervix and vagina ! Development of the urogenital sinus into the vestibule, urethra and urinary bladder
!
Embryology of the female reproductive tract development

The hymen separates the vagina (mullerian ducts) and vestibule (urogenital sinus) ! Epithelium (ecto and endo-) and some mesoderm of both original structures ! Hymen has disappeared at the time of birth ! Estrogens and testosterone influence
!
Stages of the female reproductive tract development

o
o o o
Development from around days 28-32 and a reproductive system ready at birth Growth and maturation from birth to puberty Final growth and differentiation obtained after puberty Degenerescence and fibrosis with age
Endocrine control of the female reproductive tract development

!
Embryogenesis from around days 28-32

Gonadal ridges Chromosomal Sex Gonadal Sex
Ovaries
WT-1 SF-1 DAX-1
Bipotent gonads
SRY
Testis
S cells
Phenotype Sex
Granulosa Cells SF-1 Estradiol/P4
Thecal cells SF-1 Testosterone
SF-1
Testosterone
Leydig cells
SF-1
MIS
Female Phenotype Regression Of Mullerian ducts
Male phenotype
Embryogenesis from around days 28-32
Growth and maturation from birth through puberty " Dependent on FSH, LH, estradiol, IGF, androgens Final growth obtained after puberty

!
The ovaries secrete small amounts of androgens and androgen precursors, and, additionally, estrogens stimulate external genitalia growth. From birth through puberty, these ovarian secretions induce the changes in mammary glands development, body fat deposition, vaginal and uterine tissues growth and secretions.
Spaying, depending on age at completion, removes the endocrine support needed for full reproductive development and development of the external genitalia.

#
Questions related to early spaying:

# Does
this affect external genitalia development? # Is this responsible for pathological processes in dogs? # Does age at spaying influence the appearance of those pathological processes, if any?
Since in Florida (only 2 years!) we have been impressed by the large number of dogs presented to our SA Reproduction Service at the VMC for recessed vulva and external genitalia problems. These observations are really uncommon in Europe, where early spay is exceptional.
Does early spaying influence external genitalia problems?
Any influence on - development of vaginitis, - perivulvar dermatitis, - urinary tract problems?
Recessed vulva, vaginal dermatitis, vaginitis and UTI

"
27 dogs were seen by the Small Animal Reproduction Clinic at the VMC of the University of Florida within 18 months (October 2004 through April 2006) with a history of Recurrent UTI (74%), with some cases lasting for more than 10 years!! Vaginitis (100%)
Newly diagnosed = 66% Recurrent = 27%
"
Peri-vulvar dermatitis (40%) Age at time of presentation ranged from 0.7 to 12.8 years (mean 3.2 years)

Recessed-hypoplastic vulva = 85% " Redundant skin fold = 40%
"

! !
All dogs, but 2, were spayed dogs 21 had been spayed before puberty
Mean age at spaying 4.7 +/- 3 months n=18 15 were spayed around 2 to 4 months
Mean age at spaying 11.8 +/- 3 weeks n=12 (+ 3 unknown)
6 were spayed around puberty

Mean age at spaying 7.5 +/- 0.8 months
4 had been spayed after puberty

Mean age at spaying 2.4 +/- 0.86 years

Before Puberty 15 (60%) 6 (24%) 21 (84%) After Puberty 0 (0%) 4 (16%) 4 (16%) Total 15 (60%) 10 (40%) 25 (100%)
Before 4 months After 4 months Total
Fisher's Exact Test The two-sided P value is 0.0166, considered significant. The row/column association is statistically significant.

!
All dogs have been treated at least once and sometimes for several years with AB without significant success. Dogs were surgically treated with definite resolution of the clinical signs, with the exception of one case. One major dehiscence was observed.
Discussion
" " " "
Preliminary results Higher incidence in spayed animals than in intact dogs Higher incidence in animals spayed early than in animals spayed later More common in U.S., where early spaying is actually more common than in Europe, where mean age at sterilization is around puberty (when most of the growth is achieved)
Discussion
"
" "
Older textbooks indicate that spaying performed in dogs prior to completion of puberty decreases the release of estrogen, preventing normal development of secondary sex characteristics One of the results of this process may be recessed, juvenile vulva Furthermore, BW gain being a common feature in neutered animals, redundant skin folds may be present in conjunction with recessed vulva
Discussion
" "
Our preliminary results seem to confirm those observations Contradictory opinions exist in the literature on the effect of early spaying and the reproductive tract of the female dog (e.g., Salmeri et al., 1999; Lightner et al., 2001)
! ! ! !
Not long-term Limited number of animals Intended to demonstrate the safety of early versus late spaying Anterior to 2000 when early spaying was not as common as today
10
Discussion
"
"
Recessed vulva and redundant skin folds are associated with ! Retention of fluids ! Urine leaking ! Irritation by hair ! Continuously moist area ! Bacterial growth ! Perivulvar vaginitis ! Vaginitis ! UTI Surgery is an effective method to correct the trouble
Conclusions
"
"
"
All early spayed animals shown with some of the previous clinical signs should always first be checked for hypoplastic/recessed vulva Hormonal insufficiency (including estrogens and IGF) is probably involved in the determinism of the disease For this reason, as well as for all the other related problems, early spaying should be considered with caution when not absolutely needed
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PRESENTATION SUMMARY & POWERPOINT Incontinence in Spayed Bitches: Frequency, Causes & Therapy
Iris Reichler, Madeleine Hubler and Susi Arnold, Vetsuisse-Faculty, University of Zurich, Switzerland Urinary incontinence (UI) is the involuntary loss of urine. UI rarely occurs in sexually intact bitches (0-1%)1, whereas in spayed bitches the incidence is up to 20%2. The underlying pathophysiological mechanism is a reduced closure pressure of the urethra after spaying3. The causal relationship between the removal of the ovaries and UI has been clearly demonstrated4. However, it is still unclear what mechanism triggers UI after spaying. An oestrogen deficiency was initially considered to be the underlying cause5. This hypothesis is however contradicted by several observations. For example, bitches treated with depot preparations of gestagens, to suppress oestrus, do not have an increased risk of UI, even though the treatment results in ovarian atrophy6 and the oestrogen remains in a basal level7. Another side effect of spaying is the increase in plasma gonadotropins, due to the lack of the ovarian negative feedback8. About 42 weeks after ovarectomy the gonadotropin levels reach a plateau, when the plasma FSH is 17 times and the plasma LH is 8 times the initial concentration9. One could therefore ask if it is the elevated plasma level of FSH and LH that are responsible for the increased risk of UI in spayed bitches. If this were correct, then affected bitches could be successfully treated with depot preparations of GnRHanalogues, through down-regulation of GnRH-receptors in the pituitary and this in turn will decrease the plasma gonadotropin concentrations. Indeed, 7 of 13 bitches affected by UI were successfully treated with an injection of depot preparations of GnRH-analogues and remained continent for an average of 247 days10. However, it is questionable whether the success of this treatment is due to a decrease in gonadotropins since their blood levels in responders and non-responders are not different11. It is possible that GnRH has a direct effect on the lower urinary tract, but the success of the therapy is not based on a normalisation of the urethral sphincter incompetence after spaying11. Recent studies in beagle bitches have given rise to the assumption that GnRH modulates the function of the bladder12. The treatment of incontinent bitches with GnRH-analogues is mainly interesting for the clarification of the pathophysiological mechanism. For patients affected by UI, the therapy of first choice is with alpha-adrenergica (Phenylpropanolamine / Ephedrine). This results in an increased urethral closure pressure and continence in more than 90% of cases. If the therapeutic effect is insufficient, then alpha-adrenergica may be combined with oestrogen or Flavoxatum. In refractory cases, several surgical methods are described of
Session I: Non-reproductive Effects of Spaying and Neutering which colposuspension13, urethropexy14 and the endoscopic injection of collagen15 are most common and have a success rate of 50 - 75%.
References
1. Thrusfield, Holt and Muirhead (1998) J Small Anim Pract 39:559-566. 2. Arnold et al. (1989) Schweiz Arch Tierheilk 131:259-263. 3. Rosin and Barsanti (1981) JAVMA 178:814-822. 4. Thrusfield (1985) Vet Rec 116:695. 5. Finco, Osborne and Lewis (1974) Vet Clin North Am 4:501-516. 6. El Etreby (1979) Cell Tissue Res 200:229-243. 7. De Bosschere et al. (2002) Theriogenology 58:1209-1217. 8. Olson, Mulnix and Nett (1992) Am J Vet Res 53:762-766. 9. Reichler et al. (2004) Theriogenology 62:1391-1402. 10. Reichler et al. (2003) Theriogenology 60:1207-1216. 11. Reichler et al., Theriogenology, in press (2006). 12. Reichler et al., Theriogenology, in press (2006). 13. Holt, J Small Anim Pract 26:237-246, 1985. 14. White, J Small Anim Pract, 42: 481-486, 2001. 15. Arnold et el. (1996) Small Anim Pract 37:163-168.
Session I: Non-reproductive Effects of Spaying and Neutering Incontinence: Frequency, Causes and Therapy By Dr. Iris Reichler
Urinary Incontinence (UI) in spayed bitches: frequency, causes, therapy
Iris Reichler, Madeleine Hubler, Susi Arnold Vetsuisse Faculty, University Zurich, Switzerland
UI in adult spayed bitches

Neurogenic Non-neurogenic
USMI Ureterovaginal fistula Urovagina Ectopic ureter Tumor Cystitis
UI in adult spayed bitches

Neurogenic Non-neurogenic
USMI Ureterovaginal fistula Urovagina Ectopic ureter Tumor Cystitis
Spaying - UI
Interval between spaying and UI
Immediately: 10 years Mean 2.9 years post-op 75 % of the cases within 3 years
Richter 1985, Holt 1985, Arnold 1989
Spaying - UI
Interval:
Immediately: 10 years
Incidence:
Spayed bitches 3% 21% Intact bitches 0.2 2.1%
Joshua 1965 BSAVA 1975 Krawiec 1989 Ruckstuhl 1978 Osborne 1980 Okkens 1981 Arthur 1981 Thrusfield 1985 Arbeiter 1986 Arnold 1989 Holt 1993 Blendinger 1995 Kyles 1996 Angioletti 2004 Reichler 2005 Goethelm 2006
Spaying - UI
Interval:
Immediately: 10 years
Incidence:
Spayed bitches 3% 21% Risk factors Body weight, breed Time of spaying
Ruckstuhl 1978, Arbeiter 1986, Arnold 1989, Holt 1993, Blendinger 1995, Nickel 1998, Thrusfield 1998, Stcklin-Gautschi 2001, Angioletti 2004, Reichler 2005, Goethelm 2006
Risk factors in spayed bitches

100
incontinence %
80 60 40 20 0 <10 >10-20 >20-30 >30-40 >40
Arnold 1989
Body weight
Risk factors in spayed bitches

incontinence %
Body weight Breed

100 80 60 40 20 0 Boxer DSH
Boxer Doberman Rottweiler Giant Schnauzer Old English Sheepdog
Reichler 2005
Prepubertal spay: risk 50%

incontinence %
100 80 60 40 20 0 <10 >10-20 >20-30 >30-40 >40
before first heat

Arnold 1989, Stcklin 2002
after first heat
Urethral closure pressure
Continent
18 cm H2O
Incontinent 4 cm H2O ________________________ Critical limit 7.5 cm H2O
Arnold 1997
Urethral pressure profile

Intact, continent
MUCP= 35cm H2O Spayed, incontinent MUCP= 3cm H2O
Factors contributing to urethral closure

Neuromuscular components
Somatic Sympathetic Parasympathetic 0% 50% 10%
60%
Non-neuromuscular components
Venous plexus Connective tissue 20% 20%
40%
Awad 1976, Bump 1988, Downie 1976, Rud 1980, Raz 1972
Therapy USMI
!-adrenergic substances
Phenylpropanolamine 1,5mg/kg bid, tid PO) Ephedrine (1-2mg/kg bid PO) !Continence: 85-98%
Arnold 1989, Blendinger 1995, Scott 2002, Burgherr 2006
Therapy USMI
!-adrenergic substances Oestrogens:
Increased responsiveness to alpha-agonists Cell growth and proliferation Increase of bladder threshold Continence: 60-65% Estriol 1mg /dog /day
Schreiter 1976
Therapy USMI
!-adrenergic substances Oestrogens:
Increased responsiveness to alpha-agonists Cell growth and proliferation Increase of bladder threshold Continence: 60-65% Estriol 1mg /dog /day
Hodgson 1978, Larsson 1984,Versi 1988, arnold 1997, Janszen 1997, Nickel 1998, Blakemann 2001, Mandigers 2001
Forms of UI in spayed bitches

USMI
13%
11%
combined form
23%
53%
detrusor instability
normal UPP
Nickel 1997
Combined Therapy
!-adrenergic substances & drugs for detrusor instability Anticholinergic agent (propantheline) Antispasmodic medications (oxybutynine, tolteridine, flavoxate, diphenpyraline) Tricyclic antidepressants (imipramine, doxepine) Beta agonist (terbutaline)
Combined Therapy
Phenylpropanolamine 1.5mg/kg bid-tid & Flavoxate 10mg/kg bid
&
Effect of treatment
Urethral closure! Relaxation of the bladder Compensation of the oestrogen deficit
Removal of the ovaries ! endocrine consequences?
10
Feedback
Estrogens
Hypothalamus GnRH Pituitary gland
Changes in gonadotropins following spaying

FSH [ng/mL]
120 100 80 60 40 20 0
!"
-2
10 13 16 19 22 25 28 31 34 37 40 43 46 49 52
LH [ng/mL]
20 15 10 5 0 -2 1 4
weeks post spaying
!"
7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 weeks post spaying
Reichler 2004
11
Disturbed Feedback
Hypothalamus GnRH Pituitary gland FSH, LH
? Urinary incontinence ?
FSH-, LH- and GnRHreceptors in the urinary tract
EP
SM
Welle 2006
12
GnRH treatment
35 incontinent bitches 18 continent 13 improved 4 unchanged
Reichler 2006
UPP after GnRH treatment:

Spayed incontinent
After GnRH-treatment, continent
13
Cystometry
before treatment
post GnRHtreatment
Endoscopic injection of collagen
14
Urethra Vagina
Submucosal injection of collagen
15
End of procedure
Long-term success of collagen injection

% 100
80 60 40 20 0 6 months after treatment Continent Final success Improved Incontinent
Barth 2002
16
Session I: Non-reproductive Effects of Spaying and Neutering Incontinence: Frequency, Causes and Therapy By Dr. Iris Reichler Thanks to Susi Arnold Madeleine Hubler Adrian Fairburn Andrea Barth Lisa Hung Esther Pfeiffer Monika Welle Christine Eckrich Tuulia Burgherr Wolfgang Jchle Claude Pich PR Pharmaceuticals Tim Trigg Peptech Vetsuisse Grant Grant Univ. of Zurich ESVD Grant
17
PRESENTATION SUMMARY & POWERPOINT Risks and Benefits of Neutering and Early-Age Neutering in Dogs and Cats: Effects on Development, Obesity, and Select Orthopedic and Neoplastic Conditions
C. Victor Spain, Philadelphia, Pennsylvania Neutering of dogs and cats confers a mix of benefits and adverse risks. The objective of this presentation is to highlight recent research findings on the associations between neutering (whether early-age or at a traditional age) and select medical conditions. In this abstract, the term neutering is used in the broadest sense to include both castration of male dogs and cats or ovariohysterectomy (or ovariectomy) of female dogs and cats. The data on early-age neutering is from a retrospective cohort study of 1,579 cats and 1,659 dogs adopted from a large animal shelter between 1989 and 1998 (Spain, 2004). Obesity. Several studies have indicated an increased prevalence of obesity in neutered dogs and cats. Energy consumption appears to decrease after neutering in dogs and cats, although the degree and timing varied between studies. Some researchers attribute neutering-related obesity in cats to increased food consumption and not to altered metabolic rate, suggesting that the weight gain can be prevented with a lower fat diet (German, 2006, Nguyen, 2004, Kanchuck, 2002). Obesity does not appear to be affected by age of neutering in cats, but among dogs, early-age neutering is associated with a lower incidence of obesity than neutering after 6 months of age (Spain, 2004). Canine Hip Dysplasia (CHD) and Cranial Cruciate Ligament (CCL) Injury. One study found an increased incidence of CHD after neutering in boxers (van Hagen, 2005), and among dogs seen in an orthopedic surgical clinic, the prevalence of CCL injury among neutered dogs (4.7%) was more than twice that of intact dogs (2.3%) (Slauterbeck, 2004). These findings regarding CCL injury incidence are consistent with findings that the level of sex hormones affects the incidence of anterior cruciate ligament (ACL) rupture in humans. Hip dysplasia is increased among early-neutered dogs compared to those neutered after 6 months of age (Spain, 2004). Mammary Cancer and Prostatic Cancer. Spaying before 1 year of age reduces the risk of mammary carcinoma approximately 90% in cats, and spaying before second estrus in dogs similarly reduces the risk by about 90% (Overley, 2005). The incidence of mammary cancers does not vary between ovariohysterectomy (traditional spay with removal of the uterus and ovaries) and ovarioectomy (removal of just the ovaries) (van Goethem, 2006). Traditional thought is that neutering reduces the risk of prostatic cancer among male dogs. Recent research suggests that after neutering, however, changes in endothelin, a cell protein involved in cell growth, may eventually reverse the benefits of neutering on prostatic cancer risk (Padley, 2002) and the incidence of prostatic cancer may actually be higher in castrated dogs than intact dogs (Teske, 2002).
Select References
Early-age neutering CV Spain, JM Scarlett, KA Houpt, 2004. Long-term risks and benefits of pediatric gonadectomy in cats. Journal of the American Veterinary Medical Association. 224(3): 372-379. CV Spain, JM Scarlett, KA Houpt, 2004. Long-term risks and benefits of pediatric gonadectomy in dogs. Journal of the American Veterinary Medical Association . 224(3): 380-387. CV Spain, JM Scarlett, SM Cully, 2002. When to neuter dogs and cats: a survey of New York state veterinarians practices and beliefs. Journal of the American Animal Hospital Association, 38(4): 482-488. Physical development and obesity M Hoenig, DC Ferguson, 2002. Effects of neutering on hormonal concentrations and energy requirements in male and female cats. American Journal of Veterinary Research. 63(5): 634-639. AJ German. 2006. The growing problem of obesity in dogs and cats. Journal of Nutrition. 136: 1940S-1946S. PG Nguyen, HJ Dumon, BS Siliart, et al. 2004. Effects of dietary fat and energy on body weight and composition after gonadectomy in cats. American Journal of Veterinary Research. 65(12):1708-1713. ML Kanchuck, RC Backus, CC Calvert, et al., 2002. Neutering induces changes in food intake, body weight, plasma insulin and leptin concentrations in normal and lipoprotein lipase-deficient male cats. Journal of Nutrition. 132:1730S-1732S. PD McGreevy, PC Thompson, C Pride, et al., 2005. Prevalence of obesity in dogs examined by Australian veterinary practices and the risk factors involved. The Veterinary Record. 156:695-702. Orthopedic disorders JR Slaughterbeck, K Pankratz, KT Xu, et al. 2004. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clinical Orthopedics and Related Research. 429: 301-305. MAE van Hagen, BJ Ducro, J van den Broek, et al., 2005. Incidence, risk factors, and heritability estimates of hind limb lameness caused by hip dysplasia in a birth cohort of Boxers. American Journal of Veterinary Research. 66(2):307-312. Mammary and prostate cancer RJ Padley, DB Dixon, JR Wu-Wong, 2002. Effects of castration on endothelin receptors. Clinical Science. 103(suppl. 48):442S-445S. B Overley, FS Shofer, MH Goldschmidt, et al., 2005. Association between ovariohysterectomy and feline mammary cancer. Journal of Veterinary Internal Medicine. 19:560-563.
Session I: Non-reproductive Effects of Spaying and Neutering B van Goethem, A Schaefers-Okkens, J Kirpensteijn, 2006. Making a rational choice between ovariectomy and overiohysterectomy in the dog: A discussion of the benefits of either technique. Veterinary Surgery. 35:136-143. E Teske, EC Naan, EM van Dijk, et al., 2002. Canine prostate carcinoma: epidemiologic evidence of an increased risk in castrated dogs. Molecular and Cellular Endocrinology. 197:251-255.
Session I: Non-reproductive Effects of Spaying and Neutering Effects on Growth, Hip Dysplasia, Immunology and Tumors By Dr. Vic Spain
Risks and benefits of neutering and early-age neutering in dogs and cats
Physical development Select orthopedic conditions Obesity Diabetes Select neoplastic conditions
C. Victor Spain, DVM, PhD Philadelphia Department of Public Health cvs2@cornell.edu
Objectives
!Highlight recent research findings on
associations between neuter status (or time of neutering) and select medical conditions in dogs and cats
!Note: using neuter in the broadest sense

" Castration of male dogs and cats " Ovariectomy (removal of just ovaries) or
ovariohysterectomy of female dogs and cats
Limitations/Cautions
! Wont have time to address the quality, generalpractices for a shelter or veterinary clinic
izability, and possible biases of every study cited
" If you will be using this information to shape neutering

# Review the original source articles # Contact me or another veterinary epidemiologist
! Risks/benefits may be different for ovariectomy vs.
ovariohysterectomy ! Risks/benefits may differ by age at neutering ! Any policy decision should consider the frequency and consequences of any condition
Long-Bone Development
! Dogs neutered at 7 weeks or 7 months of age had, on
average, radial lengths 2 cm longer than those left intact (Salmeri, 1991) " Pubertal sex hormones are part of the signal for growth plates to close
continue to grow later into adolescence ! For cats (Stubbs, 1996), similar delay in growth plate closure with neutering, but not statistically significant difference in bone length
" With lower sex hormone levels, the bones
Does delayed physeal closure lead to more long-bone fractures?

! Age of neutering not associated with frequency of longbone fractures (dogs or cats)
"
Animals neutered post-pubertally should be the same as those left intact (so wouldnt expect the neutered animals to be any lower risk)
! Unaware of any study indicating an association between

neutering and risk of long-bone fractures and cats in general
! Fairly low incidence of long-bone fractures in neutered dogs

"
Retrospective cohort study of 1,579 cats and 1,659 dogs adopted from a large animal shelter between 1989 and 1998 (Spain, 2004)
! At this point, appears to be a mostly theoretical concern
Cranial cruciate ligament (CCL) rupture in dogs

Prevalence of CCL (same as ACL in two-legged animals) rupture among dogs in one veterinary practice (Slauterbeck, et al., 2004)
Prevalence of CCL disease
6 5 4 3 2 1 0 Male Female
Neutered Intact
3,218 dogs Single observer not blinded to neuter status at time of assessment
Mechanism for association between CCL rupture and neuter status?
!In humans, risk of ACL rupture
associated with gender and among females, phase of the menstrual cycle !Not associated with age of neutering (Spain et al., 2004)
Canine Hip Dysplasia (CHD)

! Difficult to tease out from recent literature
" "
Many studies of CHD focus on purebred dogs, many of whom are neutered only after they have been diagnosed with a potentially heritable problem Usually neuter status is not the main focus of these studies
! In a prospective cohort study of purebred boxers, neutering

was associated with 50% increase in incidence of CHD (van Hagen, 2005)
"
Did not present proportion neutered or assess reasons for neutering (i.e. Were these dogs neutered because they had poor conformation to begin with?)
! CHD increased with neutering before 6 months of age

(Spain, 2004)
Risk of obesity increases with neutering in dogs and cats

One recent example (Kanchuk, 2002) 16 normal adult cats in laboratory setting, 8 neutered, 8 intact Fed ad libitum
7
Mean weight, Kg after 36 week
6 5 4 3 2 1 0
Neutered Intact
Obesity (cont.)
! Cats Neutering appears to be associated with increased
" "
food consumption, but not necessarily lower metabolic rate (German et al., 2006)
In laboratory setting, obesity can be prevented with lower-fat diet (Nguyen, 2004)
Is education enough to counteract effect?
Increased risk of diabetes, lameness, and certain skin conditions among obese cats (Scarlett, 1998)
Dogs Neutering before 6 months of age associated with lower prevalence of obesity (20%) compared to neutering after 6 months of age (25%) (Spain, 2004)
"
Does neutering early mitigate the increased risk of obesity associated with neutering in general?
Diabetes
! Dogs Complicated mix of risk factors
" " " " "
Different forms with different risk factors Certain breeds at higher risk Possibly secondary to certain endocrine disorders Intact bitches can have transient diabetes during pregnancy or diestrus
Rarely requires treatment
! Cats
Not aware of any studies clearly indicating that neuter status alone is associated with risk of diabetes
" More common among males " More common among neutered cats
not neuter status per se
# May be a function of decreased activity and obesity, and
Mammary Cancer (Carcinoma)
!Historic studies in Alameda County, CA,

" Based on literature review, probably no
showed strong protective effect of spaying dogs before second estrus (Schneider, 1969, 1975)
difference between ovariectomy and ovariohysterectomy (van Goethem, 2006)
!Until recently, less clear in cats

204 cases and 200 controls
" Overley et al. (2005) Case/control study of
Neutering before 1 year of age lowers the risk of mammary cancer in cats (Overley, 2005)
100 90 80 70 60 50 40 30 20 10 0 Mammary cancer Comparison cat population
Intact Neutered >1 yr Neutered <1 yr
Odds ratio for neutering before 1 year of age = 0.14
Canine Prostatic Cancer (Carcinoma)
!Traditional thought
!Recent research indicates that after castration, human cases become insensitive to androgens over time
dogs (N=6 dogs, Padley, 2002)
Percentage
" Neutering reduces testosterone levels, which
should, in turn, reduce risk of prostatic cancer " Castration has been evaluated as a treatment in human cases
" Endothelin binding increases after castration in
Castration associated with increased risk of prostate cancer (Teske, 2002 )

100 90 80 70 60 50 40 30 20 10 0 Prostate cancer Comparison dog population
Intact Neutered
Among 15,000 male dogs admitted to a teaching hospital in the Netherlands Odds ratio for neutering > 100 days before diagnosis = 2-3 4.3 Probably much lower overall incidence in dogs than humans (0.4% of admissions)
Immune status
! Difficult to assess How can we quantify the outcome?
"
Decreased immune activity could lead to increased incidence of some infections but lower incidence of autoimmune or inflammatory disorders
! Not aware of any studies clearly indicating an association

between neuter status and overall immune function
Percentage
"
Neutering procedure may be associated with exposure to infectious agents at the time of the procedure (Howe, 2001)
! Early-age neutering associated with decreased incidence of !

some inflammatory conditions in cats (Spain, 2004) Early-age neutering not associated with incidence of repeated infections, demodicosis, or pyoderma in dogs (Spain, 2004)
Summary
!Increased with
neutering
!Decreased with
neutering
" Obesity (preventable?) " CCL rupture (dogs) " Canine hip dysplasia? " Prostatic cancer (dogs)
" Mammary cancer
!Unrelated to neuter status

(or lacking evidence)
" Long-bone fractures " Diabetes " Immune status
Acknowledgements
!Dr. Jan Scarlett, Cornell University !PETsMART Charities !Kenneth A. Scott Charitable Trust
10

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Session I: Non-reproductive Effects of Spaying and Neutering

SESSION OVERVIEW Dr. John Verstegen

Session I: Non-reproductive Effects of Spaying and Neutering

BEHAVIORAL EFFECTS OF SPAYING/NEUTERING IN DOMESTIC DOGS

OFTEN CITED BEHAVIORAL REASONS TO SPAY/NEUTER A PET:

Canine Behavioral Assessment & Research Questionnaire (C-BARQ)

The C-BARQ Factors or Traits

Miscellaneous C-BARQ Items

Random Sample Survey

English Springer Spaniels

West Highland White Terriers

Shetland Rottweilers Sheepdogs

Reasons for Spaying/Neutering:

Percent 41.8 2.2 18.1 31.4 .5 6.0

SPAYED FEMALES ARE MORE AGGRESSIVE TOWARD PEOPLE

* p = 0.06 Mann-Whitney U test

SPAYED FEMALES ARE MORE FEARFUL AND SENSITIVE TO TOUCH

** p < 0.025 Mann-Whitney U test

NEUTERED MALES MARK THEIR TERRITORIES LESS OFTEN TERRITORIES

** p < 0.001 * p < 0.004 Mann-Whitney U test

BREED-SPECIFIC EFFECTS OF SPAYING/NEUTERING DOG-DIRECTED AGGRESSION/FEAR

Convenience Sample Survey

** p < 0.0001 * p < 0.0005

SPAYED/NEUTERED DOGS ARE MORE FEARFUL AND SENSITIVE TO HANDLING

* p < 0.0001 Mann-Whitney U test

SPAYED DOGS ARE LESS ENERGETIC

* p < 0.001 Mann-Whitney U test

SPAYED/NEUTERED DOGS ROLL IN & EAT FECES MORE OFTEN

* p < 0.0005 Mann-Whitney U test

NEUTERED DOGS BEG & STEAL FOOD MORE OFTEN

* p < 0.0001 Mann-Whitney U test

SPAYED/NEUTERED DOGS SELF-GROOM & BARK EXCESSIVELY

Mean (+/- 95% confidence intervals)

** p < 0.0001 * p < 0.001 Mann-Whitney U test

BREED-SPECIFIC EFFECTS OF SPAYING/NEUTERING TOUCH SENSITIVITY

SEX-SPECIFIC EFFECTS OF SPAYING/NEUTERING

* p < 0.025 ** p < 0.01 Mann-Whitney U test

Surgical neutering and the external reproductive system in the dog

Embryology of the female reproductive tract development

Embryology of the female reproductive tract development

Stages of the female reproductive tract development

Endocrine control of the female reproductive tract development

Embryogenesis from around days 28-32

Granulosa Cells SF-1 Estradiol/P4

Thecal cells SF-1 Testosterone

Female Phenotype Regression Of Mullerian ducts

Endocrine control of the female reproductive tract development

Embryogenesis from around days 28-32

Endocrine control of the female reproductive tract development

Endocrine control of the female reproductive tract development

Endocrine control of the female reproductive tract development

Questions related to early spaying:

Does early spaying influence external genitalia problems?

Any influence on - development of vaginitis, - perivulvar dermatitis, - urinary tract problems?

Recessed vulva, vaginal dermatitis, vaginitis and UTI

Recessed vulva, vaginal dermatitis, vaginitis and UTI

Recessed vulva, vaginal dermatitis, vaginitis and UTI

Recessed vulva, vaginal dermatitis, vaginitis and UTI

Recessed vulva, vaginal dermatitis, vaginitis and UTI

6 were spayed around puberty

4 had been spayed after puberty

Recessed vulva, vaginal dermatitis, vaginitis and UTI

Before 4 months After 4 months Total