University of Zurich. Gonadectomy in cats and dogs: a review of risks and benefits. Zurich Open Repository and Archive. Reichler, I M.

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1 University of Zurich Zurich Open Repository and Archive Winterthurerstr. 190 CH-8057 Zurich Year: 2009 Gonadectomy in cats and dogs: a review of risks and benefits Reichler, I M Reichler, I M (2009). Gonadectomy in cats and dogs: a review of risks and benefits. Reproduction in Domestic Animals=Zuchthygiene, 44(Suppl. 2): Postprint available at: Posted at the Zurich Open Repository and Archive, University of Zurich. Originally published at: Reproduction in Domestic Animals=Zuchthygiene 2009, 44(Suppl. 2):29-35.

2 Gonadectomy in cats and dogs: a review of risks and benefits Abstract The necessity, and in particular the timing, of gonadectomy in dogs and cats is still controversial. This is mainly because gonadectomy confers a mixture of benefits and adverse effects that depend upon the age at neutering, sex, species and breed. In this paper, the long-term risks and benefits of gonadectomy, at various ages, in dogs and cats are reviewed using data describing the effects of desexing on the urogenital tract and on other medical conditions, such as orthopaedic diseases, immune-mediated diseases, tumour development and behaviou.

3 Gonadectomy in cats and dogs: Risks and benefits Zurich, Switzerland; Surgical contraception: Pros and cons in cats and dogs; Reichler IM; Section of Small Animal Reproduction, Clinic of Reproductive Medicine, Vetsuisse Faculty University Zurich Abstract: The necessity, and in particular the timing, of gonadectomy in dogs and cats is still controversial. This is mainly because gonadectomy confers a mixture of benefits and adverse affects that depend upon the age at neutering, sex, species and breed. Long-term risks and benefits of gonadectomy, at various ages, in dogs and cats are reviewed using data describing the effects of desexing on the urogenital tract and on other medical conditions, such as orthopedic diseases, immune-mediated diseases, tumor development and behavior.

4 Contraception through surgical sterilization or gonadectomy (GX) is usually an irreversible intervention that results in a permanent cessation of the reproductive function. Surgical methods where the gonads are removed, are ovariectomy (OVE) or ovariohysterectomy (OVH), through the linea alba or via the flank or laparoscopy (Davidson et al. 2004; Devitt et al. 2005). In contrast to the removal of the gonads, the sterilization by means of a vasectomy, salpingectomy and hemiovariohysterectomy also results in the elimination of reproductive function, but the sexual behavior and the incidence of diseases transmitted by sexual hormones are not influenced. GX to control pet overpopulation Until now, GX is the contraceptive technique of choice. As GX is irreversible, spay programs are widely accepted for population control. In spite of worldwide efforts to reduce pet overpopulation, the number of dogs and cats is still increasing (New 2006). Researchers world wide are searching for a single and simple contraceptive method that results in the permanent elimination of reproduction, but at significantly less cost than neutering. In male dogs this can be achieved by the intratesticular injection of zinc gluconate (Levy et al. 2008). Spaying of female dogs and cats is still recommended to avoid high population densities, animal suffering and the spread of zoonosis. The castration of tomcats is also recommended, because castrated cats have on average better health and a reduced mortality rate than intact cats (Kalz 2001). The necessity, and in particular the timing, of GX in dogs and cats kept as pets is still controversial. This is mainly because GX confers a mixture of benefits and adverse affects depending on age at neutering, sex, species and breed. Spain therefore claims: Any policy decision should consider the frequency and consequences of any condition (Spain 2006). Effect of spaying on the reproductive tract

5 In some countries OVH is the preferred technique for spaying dogs. This preference was most likely based on the presumption that future uterine pathology is prevented by removing the uterus. However, historical reviews of the short-term and long-term complications after OVH and OVE leads to the conclusion that there is no benefit and thus no indication for removing the uterus during routine neutering in healthy bitches (Okkens et al. 1997; van Goethem et al. 2006). At our clinic OVH is only performed in older females or females treated with gonadal steroids. With the removal of the gonads, diseases such as ovarian tumors and cysts no longer occur. Furthermore, spayed dogs and cats are no longer susceptible to disorders mediated by ovarian hormones, such as vaginal hyperplasia or metropathies. In spayed dogs and cats metropathies are virtually non-existent, whereas are common in intact or progestagen treated animals. In Sweden approximately 7% of all bitches are spayed and a study showed that almost 25% of all registered dogs up to 10 years of age developed a pyometra (Hagman 2004). In addition, in 5 year old queens there was a significant likelihood of clinical evidence for uterine disease (Potter et al. 1991). Effect of GX on the development of tumors of the reproductive tract Sparing effect of spaying on the development of mammary tumors (MT): MT are the most common tumors found in female dogs, with estimates of a lifetime risk for developing malignant MT ranging from 2% to more than 20% (Dorn et al. 1968; Moulton et al. 1986). In cats, the incidence is less than half that of dogs. However, these tumors account for 17% of neoplasms in female cats, (Dorn et al. 1968; Hayes et al. 1981; Patnaik et al. 1975; Schmidt and Langham 1967) and at least 85% of feline MT are malignant (Bostock 1986; Hayes et al. 1981; Schmidt and Langham 1967). There is some evidence supporting a breed-associated predisposition: Siamese cats, Domestic shorthair cats, several Spaniel and Poodle breeds and the Dachshund seem to be predisposed. Apart from the genetic predisposition, gonadal hormones appear to mainly influence the pathogenesis of MT. Spayed dogs and cats are

6 significantly less affected by MT than intact animals, but the timing of spaying also plays a critical role. The risk of developing malignant MT in dogs spayed prior to the first estrus is reduced by 99.5 % compared to intact dogs. Dogs spayed after the first and before the second estrus had a 92% reduction in the risk of malignant MT development compared to intact dogs. According to the study by Schneider et al. the sparing effect of GX on the development of malignant MT is lost after females have cycled more than twice or are older than 2.5 years of age (Schneider et al. 1969). However, the risk for benign MT development appears to be reduced by GX even at a later age (Phillips 2002). Similar effects are seen in cats: Cats spayed prior to 6 months of age had a 91% reduction in the risk of malignant MT development compared to intact cats. Those spayed prior to 1 year of age had an 86% reduction in risk, those spayed between 12 and 24 months of age had an 11% risk reduction, but after 24 months of age there was no benefit (Overley et al. 2005). GX and survival rate after MT removal: According to several studies, performing an OVE or OVH at the time of or after MT excision does not significantly affect the survival time (Morris et al. 1998; Philibert et al. 2003; Schneider et al. 1969; Yamagami et al. 1996). In contrast other authors suggest, that OVH may be an effective adjunct to MT removal in dogs with mammary gland carcinoma and that the timing of the OVH plays a critical role in survival time. Dogs spayed within 2 years of the development of their malignant tumors had a survival advantage over intact dogs or those spayed more than 2 years prior to MT development and mastectomy (Sorenmo et al. 2000). Effect of spaying on tumors of the genital tract: In general, tumors of the genital tract are rare in spayed dogs and cats. Most canine uterine, canine and feline vaginal and vulvar tumors are leiomyomas. Because the occurrence of leiomyomas is mainly reported in intact female dogs and cats (Kydd and Burnie 1986; Stein 1981; Thacher and Bradley 1983; Wolke 1963) and these tumors were not seen in bitches ovarectomized before 2 years of age (Brodey and Roszel 1967), a hormonal influence is strongly suspected. Furthermore, OVH at the time of

7 tumor removal may be beneficial. In a review no bitches undergoing concurrent OVH had recurrence of vaginal or vulvar neoplasia (Thacher and Bradley 1983). Effect of spaying on external genitalia: Gonadal hormones are responsible for the normal development of the external genitalia. The effect of GX, and especially the time of GX, on the size of the vulva was examined in 3 groups of bitches and female cats. In cats and dogs gonadectomized at 7 weeks or 7 months, the vulva was small and infantile compared to that of intact females (Root et al. 1997; Salmeri et al. 1991). In these studies no clinical problems were evident. However in dogs, perivulvar dermatitis is thought to develop more commonly in obese bitches that have an infantile vulva. The incidences of recessed vulva, perivulvar dermatitis and vaginitis are higher in spayed than in intact dogs and the incidence may even be higher in females spayed as puppies (Verstegen-Onclin 2006). Vaginitis may occur as so-called juvenile vaginitis, or subsequent to vaginal atrophy following GX. Whether the spaying of bitches with juvenile vaginitis will cause chronic vaginitis persisting to adulthood or even lifelong is controversial. In a review of 37 dogs with juvenile vaginitis, 84 percent of the cases resolved with or without treatment (Johnson 1991). Allowing bitches with juvenile vaginitis to go through an estrous cycle may hasten resolution. However, it is unknown what effect increasing age and maturation of the immune system will have on the resolution of juvenile vaginitis. Effects of testicular removal on the genital tract Apart from the permanent suppression of reproductive function, bilateral orchiectomy has a prophylactic and therapeutic effect on androgen dependent diseases, such as benign prostate hyperplasia (BPH), chronic prostatitis, perineal adenomas and perineal hernias. In fact 50% of intact dogs exhibit histological evidence of BPH by 5 years of age (Berry et al. 1986). In addition, BPH predisposes dogs to prostatitis, thus for both conditions castration is a suitable treatment. Castration also prevents testicular and epididymal disorders, such as neoplasia,

8 torsion of the spermatic cord, orchitis and epididymitis. This is especially important in male dogs as the testicles are the second most common anatomical sites for cancer development (Hayes and Pendergrass 1976). These diseases are very rare in tomcats. Prostate cancer (PC): PC is rare in dogs (less than 0.6% in necropsy studies) and very rare in cats, but is almost always malignant (Weaver 1981). Castration has been evaluated as a treatment in human cases. The traditional thought was that GX reduces testosterone levels, which should in turn reduce the risk of prostate cancer. However, although PC begins as an androgen-dependent tumor, the beneficial effects of androgen deprivation are often temporary and the development of an essentially incurable therapy-resistant PC seems to be almost inevitable during later stages. In 1987, a study showed that castration at any age had no sparing effect on the risk of developing PC in dogs (Obradovich et al. 1987). Furthermore, eight cases of PC were described in cats: all but one had been castrated (Caney et al. 1998; Carpenter et al. 1987; Hawe 1983; Hubbard et al. 1990; LeRoy and Lech 2004). Over the last 5 years, several studies in dogs have identified an increased risk of neutered dogs to develop PC (with an odds ratio of 2.84 for all prostate tumors) (Bryan et al. 2007; Sorenmo et al. 2003; Teske et al. 2002). Compared to intact dogs with PC, neutered dogs with PC were more likely to fall into an older age category (Bryan et al. 2007). Apart from the reproductive status, the breed also affects the risk of developing prostate tumors. Risk varies with breed, suggesting that genetics play a role in the development of prostate tumors (Bryan et al. 2007). Neutered mix-breed dogs, Shetland sheepdogs, Scottish terriers, Beagles, English Springer Spaniels, German shorthaired pointers and West Highland white terriers had significantly higher odds than the background population of neutered dogs to have prostate cancer (Bryan et al. 2007). Effects of the timing of testicular removal on the genital tract were investigated in male cats and dogs neutered at 7 weeks, 7 months and compared with intact males (Root et al. 1997; Salmeri et al. 1991). The most striking differences in the development of secondary sex

9 characteristics were the immaturity of the prepuce, penis and os penis of male dogs neutered as puppies and the missing penile spikes in neutered cats. Effects of GX on the lower urinary tract Urinary incontinence (UI): The risk of UI is low in intact bitches. The incidence of UI due to spaying varies between 3 and 21%, depending on the author (Angioletti et al. 2004; Arnold et al. 1989; B.S.A.V.A. 1975; Blendinger et al. 1995b; Holt 1985; Joshua 1965; Okkens et al. 1997; Okkens et al. 1981; Osborne et al. 1980; Reichler et al. 2005; Ruckstuhl 1978; Stöcklin- Gautschi 2000; Stocklin-Gautschi et al. 2001; Thrusfield 1985). UI after spaying can occur immediately or up to 10 years after surgery, about 75% of the bitches become incontinent within 3 years after GX (Arnold et al. 1989). In most cases the cause for UI after spaying is a reduction in the urethral closure pressure (Arnold 1997). The risk for urinary incontinence is influenced by various factors such as body weight or breed and time of spaying. Dogs weighing less than 20 kg have a risk below 10% of becoming incontinent after spaying, whereas in dogs weighing more than 20 kg, the risk is up to 30% (Arnold et al. 1989; Reichler et al. 2005). Boxers, Dobermans, Bobtails, Giant Schnauzers and Rottweilers all have a known predisposition for UI. Spaying shortly before puberty seems to reduce the risk by 50% (Arnold et al. 1989; Reichler et al. 2005; Stöcklin- Gautschi 2000). In another study, bitches were significantly more likely to develop UI when spayed at less than 3 months of age than bitches spayed between 3 months and one year of age (Spain et al. 2004b). The pathophysiology of urinary incontinence is still unclear. Altered GnRH, FSH and LH secretion after GX (Ponglowhapan et al. 2007; Reichler et al. 2006a; Reichler et al. 2003; Reichler et al. 2005; Reichler et al. 2006b; Reichler et al. 2004; Reichler et al. 2007) may be involved. In most cases, UI due to spaying is easily controlled with the treatment of alphaadrenergic substances (Awad et al. 1978; Blendinger et al. 1995a).

10 FLUTD: A recent survey of veterinary surgeons in practice, When to neuter dogs and cats, found that the most common medical concern raised was the possibility of increased risk of FLUTD with early neutering (Spain et al. 2002). Numerous studies have been performed to examine the effect of GX on urinary health in cats, most failing to detect a correlation between GX of cats at any age and an increase in incidence of FLUTD or other problems associated with this condition. GX had no effect on urethral function in cats, as determined by urethral pressure profiles (Stubbs et al. 1996). Furthermore, similar urethral diameters, as well as no difference in pre-prostatic and penile urethra, were found in cats neutered at 7 weeks, 7 months or those remaining intact (Root et al. 1997). A long-term study performed to compare effects of prepubertal and traditional-age GX found no increased risk of FLUTD in earlyneutered cats up to 3 years after surgery (Howe et al. 2000). However, in one large study of male and female cats, both GX and obesity were found to be risk factors for the development of FLUTD (Lekcharoensuk et al. 2001). Transitional cell carcinoma (TCC): TCC rarely occurs, however there is considerable variation in the risk of canine TCC. Epidemiological studies of TCC in dogs have revealed a number of risk factors, including breed, female gender, reproductive status, and obesity, as well as environmental factors, such as insecticide exposure (Knapp et al. 2000). Scottish terriers have a 18-fold increased risk compared with mixed breeds. Females have a 2-fold increased risk compared to males; GX increases the risk more than four times in females than in male dogs (Knapp et al. 2000). The increased risk for developing TCC in neutered dogs of both sexes is not explained at this time. Effect of GX on metabolism Body weight: Although obesity can occur in both neutered and intact animals and is influenced by a number of factors such as diet, breed, and activity level, there is data indicating that neutered animals may gain significantly more weight compared to intact

11 animals. While results of several studies indicate that neutering is a risk factor for obesity in cats (neutered cats are 3.4 times more likely to become obese than sexually intact cats) (Fettman et al. 1997; Kanchuk et al. 2002; Nguyen et al. 2004), there is conflicting information on whether dogs are more likely to experience weight gain after neutering (Edney and Smith 1986; Houpt et al. 1979; Jeusette et al. 2004; Le Roux 1983). The time of GX is also controversially discussed: In a 15 months prospective study performed to compare the effect of early and traditional age neutering of intact animals, no differences in food intake, weight gain or back-fat depth among neutered and intact animals were found (Salmeri et al. 1991). However, the results of a recent population study indicate that neutering of dogs before 6 months of age is associated with lower prevalence of obesity compared to neutering after 6 months of age (Spain et al. 2004b). These results raise the question if early spaying reduces the increased risk of obesity after neutering in general (Spain et al. 2004b)? Obesity is not necessarily a consequence of GX, but it is important to control the body weight in neutered animals because of its association with increased risk of other medical problems (Lekcharoensuk et al. 2001) and the negative effects on the life expectancy (Greer et al. 2007). Obesity can be prevented by simple measures. There is evidence that cats on high dietary fat, but not carbohydrate, gain weight (Backus et al. 2007). A low fat diet alone is however insufficient to prevent obesity after GX, as it requires the feeding of carefully controlled meals and not ad libitum (Nguyen et al. 2004). Diabetes mellitus (DM): Neutered cats are not only at a higher risk of becoming obese but also have a 2 to 9 fold increased risk of developing DM than sexually intact cats (McCann et al. 2007; Panciera et al. 1990; Prahl et al. 2007). The increased probability that cats will develop obesity and DM after GX may be due to decreased insulin sensitivity (Hoenig and Ferguson 2002; Kanchuk et al. 2002). A possible increase in the risk of developing DM was detected in castrated dogs. The possible association with obesity was not defined (Marmor et al. 1982). In intact bitches an

12 altered glucose metabolism, induced by progesterone, occurs during pregnancy, metestrus and after progestin administration. Spaying is an integral part of the treatment of DM in these females. Hypothyroidism: Two studies showed that neutering was the most significant genderassociated risk factor for the development of hypothyroidism (Milne and Hayes 1981; Panciera 1994). However in another study, using age matched controls and TSH response test results, neutering had no apparent effect on the likelihood of a dog being hypothyroid (Dixon and Mooney 1999; Dixon et al. 1999). Effects of GX on the musculoskeletal system Growth: The effect of GX on skeletal growth was already well known as eunuchoid growth in antique history. Studies examining the effects of GX and timing of GX, showed that the growth rate is unaffected, but physeal closure is delayed (Root et al. 1997; Salmeri et al. 1991). This is most obvious in male cats: Male cats neutered at 7 weeks or 7 months have on average final radial lengths of 13% greater than intact males (Root et al. 1997). It is controversial if this altered growth rate has an effect on soundness. Fractures: In cats, spontaneous femoral capital physeal fractures have been suggested to be a result of delayed physeal closure related to early neutering. In retrospective studies, 39 cats with 47 fractures were examined (Craig 2001; Fischer et al. 2004; McNicholas et al. 2002). Four risk factors for spontaneous femoral capital physeal fractures in cats older than one year were suggested: Gender and reproductive status, delayed physeal closure and abnormally high body weight. Obese neutered male cats may be predisposed to femoral capital physeal fractures, which in turn emphasize the importance of controlled feeding in early neutered cats. Population studies provide no association between age at GX and incidence of fractures in either cats or dogs (Spain et al. 2004a; b).

13 Canine Hip dysplasia (CHD): There is a possible influence of GX on the development of CHD. Neutered Boxers, with a mean age of 3 years at neutering, were 1.5 times as likely to develop CHD as sexually intact dogs (van Hagen et al. 2005). However, body weight was not included in this analysis, and there is no data on the influence of the timing of GX (van Hagen et al. 2005). In a recent population study the influence of age at GX on development of CHD was also examined. Puppies that underwent GX before 5.5 months of age had a 6.7% incidence of CHD, while those between 5.5 months and 1 year of age had an incidence of 4.7%. The authors speculated that this increased incidence may have resulted from altered hip joint conformation secondary to increased bone length(spain et al. 2004b). However, considering the lower rate of euthanasia among early-age gonadectomized dogs with CHD in comparison to those that underwent later GX the author suggested that early-age GX may be associated with a less severe form (Spain et al. 2004b). Cranial cruciate ligament rupture (CCLR): GX has an influence on the prevalence of CCLR. The prevalence of CCLR is most common in neutered males, followed by spayed females, while intact animals have only half of the risk (Slauterbeck et al. 2004). No data is provided on the body weight. Osteosarcoma: Osteosarcoma is a rare but highly malignant tumor, occurring mainly in large dogs (Ru et al. 1998; Tjalma 1966). Risk factors, such as increasing age, body weight, body size and GX, were established (Cooley et al. 2002; Priester and McKay 1980; Ru et al. 1998). A study comparing 3062 purebred dogs with osteosarcoma and 3959 purebred dogs without osteosarcoma, revealed a two-fold increased risk of osteosarcoma among neutered dogs when compared to intact dogs (Ru et al. 1998). As the data did not include the age at GX, this study could not evaluate bone sarcoma risk in terms of duration of gonadal hormone exposure. To test the hypothesis that endogenous sex hormones significantly influence bone sarcomagenesis, a study of Rottweiler dogs, a breed known to be at high risk for bone sarcoma, was performed (Cooley et al. 2002). Bone sarcoma was diagnosed in 12.6% of dogs

14 in this cohort overall, with neutered dogs having a two-fold increased risk. However, gonadectomized female and male dogs lived longer than sexually intact dogs. The longer life expectancy may contribute to a higher overall cancer incidence in neutered animals. A significant association between gonadal hormone exposure and risk of bone sarcoma was found. In males castrated before 1 year of age (lowest gonadal exposure) the risk for bone sarcoma was almost four times greater than in sexually intact males. In females spayed before 1 year of age bone sarcoma incidence was more than three times greater than the rate in sexually intact females. The risk factor of early GX was found to be independent of adult height or body weight. Effects of GX on various conditions Cardiac tumors have an overall incidence of 0.19% in dogs and % in cats. Cardiac tumors occurred with similar frequency in male and female dogs, but the relative risk of developing a heart tumor for spayed females was > 4 times that of intact females (Ware and Hopper 1999). Castrated males had only a slightly greater risk (1.6 times) of developing a heart tumor than intact males. No data is provided on the age at GX. However, as most dogs with cardiac tumor were older than 10 years and data on the age of the control population is missing, a possible effect extended life expectancy of neutered dogs, compared to intact dogs, on the incidence of tumors cannot be excluded. Diseases that are transmitted by mating or copulation, such as Sticker Sarcoma or brucellosis, are rarely observed in neutered dogs. FeLV and FIV are transmitted by mating, along with other direct social contacts. It is well known that castration reduces the territorial area and behavior (Kalz 2001), but these diseases can also be transmitted by using the same feeding places. The time of GX does not seem to have an effect on the incidence of these diseases (Howe et al. 2000).

15 Life expectancy: It is well documented that neutered animals live longer than intact animals (Greer et al. 2007; Kraft 1998). The increased life expectancy in gonadectomized animals may be due to the preventive effect on diseases of the reproductive tract and/or the reduced risk-associated behavior. However, the increased life expectancy may also reflect to some extent the enhanced care of neutered animals by their owners. References Angioletti A, De Francesco I, Vergottini M, Battocchio ML, 2004: Urinary incontinence after spaying in the bitch: incidence and oestrogen-therapy. Vet. Res. Comm. 28 Suppl Arnold S, 1997: [Urinary incontinence in castrated bitches. 2. Diagnosis and treatment]. Schweiz. Arch. Tierh Arnold S, Arnold P, Hubler M, Casal M, Rüsch P, 1989: [Urinary incontinence in castrated bitches: incidence and breed disposition]. Schweiz. Arch. Tierh Awad SA, Downie JW, Kiruluta HG, 1978: Alpha-adrenergic agents in urinary disorders of the proximal urethra. Part I. Sphincteric incontinence. Brit. J. Urol B.S.A.V.A., 1975: Congress report. Sequelae of bitch sterilization: regional survey. Vet. Rec Backus RC, Cave NC, Keisler DH, 2007: Gonadectomy and high dietary fat but not high dietary carbohydrate induce gains in body weight and fat of domestic cats. Br. J. Nutr Berry SJ, Coffey DS, Strandberg JD, Ewing LL, 1986: Effect of age, castration, and testosterone replacement on the development and restoration of canine benign prostatic hyperplasia. Prostate Blendinger C, Blendinger K, Bostedt H, 1995a: [Urinary incontinence in castrated female dogs. 2. Therapy]. Tierarztl. Praxis Blendinger C, Blendinger K, Bostedt H, 1995b: [Urinary incontinence in spayed bitches. 1. Pathogenesis, incidence and disposition]. Tierarztl. Praxis

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