2017: Determining optimal age for gonadectomy in the dog: a critical review of the literature to guide decision making Determining optimal age for gonadectomy in the dog: a critical review of the literature to guide decision making Margaret V. Root Kustritz,a Margaret R. Slater,b G. Robert Weedon,c Philip A. Bushbyd aCollege of Veterinary Medicine, University of Minnesota, St. Paul, MN; bAmerican Society for the Prevention of Cruelty to Animals, Northampton, MA; cCollege of Veterinary Medicine, University of Illinois, Urbana, IL; dCollege of Veterinary Medicine, Mississippi State University, Starkville, MS Abstract Gonadectomy is the most common elective surgery performed on dogs in the United States. Concerns have been expressed by veterinarians, dog breeders, and pet owners or guardians about the need to better understand effects of gonadectomy on individual animal health. Many studies to date on this topic have been performed on small or unique populations of dogs and data from those studies may or may not readily be extrapolated to dogs seen by veterinarians in private practice. Veterinarians should be careful to read manuscripts in their entirely whenever possible rather than to rely on brief summaries that do not permit the reader to make their own decisions regarding value of the data as presented to their clinical practice. Keywords: Gonadectomy, ovariohysterectomy, castration, lifespan, neoplasia, orthopedics Introduction Proposed benefits and detriments of spay and castration surgeries in dogs have been reported in a growing body of literature over the last 20 years. Some of the data are contradictory or are difficult to reconcile with known pathophysiology. Some of the papers have received a great deal of coverage in the popular press, leading to inappropriate attention to limited data points. This manuscript is a review of the current literature on this topic, an argument for better attention to detail about published studies by veterinarians before extrapolating small data sets to all populations, and a discussion of some options about how best to present information from the literature to clients. Gonadectomy is the most common elective surgery performed on dogs in the United States, with reported prevalence of 67% in female dogs and 61% in male dogs.1 It is recommended that all animals surrendered to humane organizations should undergo gonadectomy prior to adoption for purposes of population control.2 Large review articles on the topic of determining optimal age of spay / castration surgery in dogs have been published over the last ten years.3-6 Concerns have been expressed by veterinarians, dog breeders, and pet owners or guardians about the need to better understand effects of gonadectomy on individual animal health. A review of pet owners’ needs for information regarding the decision whether or not to neuter their animal demonstrated that clients desire information regarding positive and negative pet health and welfare outcomes.7 To best meet needs of dog owners, veterinarians must maintain an awareness of studies published and, most critically, the value they bring to the question of suitable age for gonadectomy in dogs. The question about impact of gonadectomy on health is one of causation: does gonadectomy at certain ages cause or prevent specific health issues? Answering this type of question requires a large body of high quality data of varying types ranging from laboratory studies to clinical trials and observational studies of populations. No single study can prove causation. Many studies to date on this topic have been performed on small or unique populations of dogs and data from those studies may or may not readily be extrapolated to dogs seen by veterinarians in private practice. Conclusions about causation are less likely to be true when there are few studies in a given field, when samples sizes are very small, when differences between groups are small, when the study subjects are not similar to animals seen in private veterinary practice, when not enough attention is paid to confounding effects, and when measurement error is present (Table 1).8,9 Researchers, manuscript reviewers, and readers of publications must be aware of possible biases in measurement and must pay attention to whether or not findings that are statistically significant have any practical implications in veterinary practice. Peer-reviewed Clinical Theriogenology • Volume 9, Number 2 • June 2017167 publications should include an in-depth assessment of the study limitations and generalizability; studies which do not provide this should be assessed with extra caution. Veterinarians should be careful to read manuscripts in their entirely whenever possible rather than to rely on brief summaries that do not permit the reader to make their own decisions regarding value of the data as presented to their clinical practice. Current information from the literature The association between intact status and behavior in dogs is complex. This review will focus on medical concerns and will not address effect of gonadectomy on behavior. Data from the studies below may be described as relative risk, hazard ratios or odds ratios (OR). A relative risk is the likelihood that an event will occur after a specific exposure. Interpretation is the following: a relative risk of 2.0 means that a dog that has been gonadectomized is twice as likely to develop the condition as is an intact dog. Specifically, a relative risk is the ratio of the risk of developing the condition in gonadectomized dogs to the risk of developing the condition in intact dogs. The odds ratio is typically interpreted similarly to the relative risk; specifically the odds ratio is the odds of the condition in the gonadectomized dogs divided by the odds in intact dogs. Hazard ratios are similar but compare the hazard of an event or death and assume that risk is constant over time. Put another way, we can say that if the relative risk or the odds ratio is 1.0, the risk (odds) in the exposed animals equals the risk (odds) in the non-exposed animals. If the RR (OR) is greater than 1.0, the risk (odds) in exposed animals is greater than the risk (odds) in non-exposed animals. If the RR (OR) is less than 1.0, the risk (odds) in exposed animals is less than the risk (odds) in non-exposed animals. All of these values have 1 as the “no difference” value and should be accompanied by a confidence interval, which is the range of values defined with a specific probability that the “real” value lies within that range. Mammary neoplasia Reported incidence of mammary gland tumors in dogs is 3.4% with some select populations reporting incidence as high as 13% by ten years of age.10,11 Mammary neoplasia is the most common form of cancer in female dogs based on data from several large European cancer registries.12-15 Increasing age and breed are risk factors for development of mammary neoplasia.10,16-19 Age at time of diagnosis does not vary between spayed and intact dogs.20 Being thin as a young dog is reported to be protective.20 High fat diet and obesity have not been demonstrated to increase risk of development of mammary neoplasia in dogs.20 There are six studies in the literature reporting an association between gonadectomy and mammary neoplasia in dogs, with five of those studies documenting decreased incidence (Table 2). These studies report that bitches that are spayed are one-third to one-half less likely to develop tumors than are bitches that are left intact, and that bitches that remain intact are seven times more likely to develop tumors than are spayed bitches.17,19 Benefit of spaying is increased with younger age or decreasing number of heat cycles prior to spay, with a classic paper describing female dogs as having 0.5% the risk of intact dogs if spayed before their first heat, 8% the risk if spayed between their first and second heat, and 26% if spayed after their second heat.20,21 In general, greatest benefit is described for any bitch spayed before 2.5 years of age with a decreasing benefit up to nine years of age.20,22 No difference was shown between intact and spayed dogs in one study, which evaluated dogs of one breed presented to a specialty hospital.23 A systematic review of effect of gonadectomy on incidence of mammary neoplasia concluded that there was insufficient evidence to support any connection.24 Systematic reviews are analyses of all of the published literature on a given topic performed in a repeatable and objective fashion and strive to identify bias that would nullify results of published studies.25 Of the 13 studies they chose to include in their initial analysis, nine were deemed to have a high risk of bias and four to have a moderate risk of bias. The inability to identify a connection in that systematic review was more a reflection of the lack of depth in the veterinary literature on this topic than a true evaluation of the association between gonadectomy and mammary neoplasia. Hormonal stimulation is assumed to be the cause of mammary neoplasia in dogs. Eighty percent of mammary tumors and 95% of normal mammary tissues have estrogen receptors, progesterone Clinical Theriogenology • Volume 9, Number 2 • June 2017 168 receptors, or both.26 Studies differ regarding correlation of estrogen and progesterone receptors with type of tissue, with some studies suggesting that there are fewer receptors as tumors become less differentiated.26,27 An association has been reported between treatment with exogenous progestins and increased incidence of mammary tumors.18 Mammary neoplasia may be more common in bitches that had multiple episodes of overt pseudopregnancy with lactation, suggesting either a hormonal effect or the possibility of malignant transformation of mammary tissue that is metabolically active and undergoes the physical changes associated with lactation.22 Prostatic neoplasia Reported incidence of prostatic carcinoma is 0.2-0.6%.28,29 It is difficult for pathologists to differentiate prostatic adenocarcinoma, which arises directly from glandular tissue, from invasion of transitional cell carcinoma from the prostatic urethra into the prostatic parenchyma. Data presented encompasses both forms of prostatic carcinoma, a limitation in understanding the disease process. Incidence is reported to be increased in some breeds.28,30 Evaluation of other factors for association with incidence of prostatic carcinoma, including diet, activity level, housing, and exposure to tobacco smoke, failed to demonstrate any significant associations.31 There are five studies in the literature evaluating association between gonadectomy and prostatic neoplasia, with four showing increased incidence with gonadectomy (Table 3). Mean and median age at the time of diagnosis may vary between castrated and intact dogs, with one study demonstrating disease in castrated dogs at an older age compared to intact dogs.30 No study to date has demonstrated any sparing effect dependent on age at the time of gonadectomy.28-33 The cause-and-effect relationship between gonadectomy and prostatic carcinoma has not been defined. Prostatic tumors in dogs arise from ductal / urothelial tissues, which are androgen-independent.28 It may be that testosterone exerts a carcinogenic effect earlier in life.29 Because of the great variability reported in time from castration to diagnosis of prostatic neoplasia, it has been suggested that castration does not promote tumor formation but instead promotes tumor progression.28 It may be that lack of testosterone after castration is associated with atrophy of androgen-dependent tissues in the prostate and less inhibition of growth of androgen-independent tissues.34 Epigenetic effects associated with silencing of genes associated with function of androgen receptors have been demonstrated in humans with prostatic neoplasia.30 Finally, superoxide dismutase activity declines in prostatic tissue by six months after castration, suggesting a lack of response to the toxic effects of reactive oxygen species, which could be associated with oncogenesis.35 The authors are unaware of any published research documenting these phenomena in dogs. Transitional cell carcinoma (non-prostatic) Incidence of transitional cell carcinoma is at most 1%.36 Predisposing factors previously reported include increasing age, breed, and exposure to environmental herbicides and insecticides.37,38 There are two studies documenting increased incidence of transitional cell carcinoma related to neutering in dogs (Table 4).30,37,39 One study evaluated dogs of only one breed and that breed has a hereditary predisposition to transitional cell carcinoma, making extrapolation to other populations of dogs difficult.37 The cause-and-effect relationship between gonadectomy and transitional cell carcinoma has not been defined. Osteosarcoma Incidence of canine osteosarcoma is <0.1%.19 Factors reported to be associated with incidence of osteosarcoma include increasing age, breed and increasing size.40-42 There are four studies in the veterinary literature specifically addressing effect of gonadectomy on incidence of osteosarcoma with three showing increased incidence and one showing no effect (Table 5).23,40,42,140 Two studies evaluated dogs of only one breed, and one evaluated Rottweilers a breed that has a hereditary predisposition to osteosarcoma, making extrapolation to other populations of dogs difficult.42 The cause-and-effect relationship between gonadectomy and osteosarcoma has not been defined. Clinical Theriogenology • Volume 9, Number 2 • June 2017169 Hemangiosarcoma Reported incidence of hemangiosarcoma is 0.2%43. Predisposing factors previously reported include increasing age and breed; there is no variation in prevalence between female and male dogs.43-46 There are seven studies describing relationship between gonadectomy and hemangiosarcoma (Table 6). Splenic and cardiac hemangioma and hemangiosarcoma were reported to be more common in spayed females than in intact females.43,45,140 Castrated males had a slightly increased risk of developing a heart based tumor compared to intact males.43 Hemangiosarcoma was reported to occur more commonly in females spayed after 12 months of age than in females spayed early or left intact in one study and to be more common in females spayed at less than six months or more than 12 months in another study; there was no reported effect of castration in male dogs in either study.47,48 Several studies have reported raw data showing numbers of affected spayed females, intact females, castrated males, and intact males with hemangiosarcoma in specific breeds using data drawn from records of a referral hospital, with varying amounts of statistical analysis.23,47,49 It can be difficult to assess the value of raw data without more complete information about the population of dogs presented to that hospital. Referral hospitals see a unique population of dogs, generally those with non-standard or complicated disorders, often owned by individuals who have disposable income available for advanced care for their dog, and perhaps more likely to be related as they tend to be drawn from a specific geographic region.50 The cause-and-effect relationship between gonadectomy and hemangiosarcoma has not been defined in dogs. One hypothesized association is alteration in immune function with gonadectomy including decreased immune surveillance for cancer cells due to lack of sex steroids.48 The authors are unaware of any published research documenting this phenomenon in dogs. Lymphoma Reported incidence of lymphoma in dogs is 1.1%.15 There is a hereditary component, increasing age is a risk factor, and environmental factors also may play a role in tumor development.15,51 There are six reports evaluating the effect of gonadectomy on incidence of lymphoma with conflicting results (Table 7). Five studies showed increased risk with two studies showing increased risk in females only and two reports showing a difference in males only.47-49,51 Several studies have reported raw data showing numbers of affected spayed females, intact females, castrated males, and intact males with lymphoma in specific breeds using data drawn from records of a referral hospital, with varying amounts of statistical analysis.23,47,49 Concerns are as described for hemangiosarcoma. The cause-and-effect relationship between gonadectomy and lymphoma has not been defined in dogs. Hypothesized associations include a possible protective effect of estrogens, and alterations in immune function with gonadectomy including decreased immune surveillance for cancer cells due to lack of sex steroids.48,51 The authors are unaware of any published research documenting these phenomena. Cutaneous mast cell tumor Prevalence of mast cell tumors in a study evaluating information submitted to an electronic database by a large number of private practices was 0.27%.52 Some breeds are reported to be at increased risk.52,53 There are seven reports evaluating association between gonadectomy and mast cell tumors, with conflicting conclusions. Five reported increased incidence with gonadectomy (Table 8). Two studies demonstrated increased incidence with gonadectomy only in females.49,53 Several studies have reported raw data showing numbers of affected spayed females, intact females, castrated males, and intact males with mast cell tumor in specific breeds using data drawn from records of a referral hospital, with varying amounts of statistical analysis.23,47,49 Concerns are as described for hemangiosarcoma. The cause-and-effect relationship between gonadectomy and mast cell tumor has not been defined in dogs. Hypothesized associations include alterations in immune function with gonadectomy including decreased immune surveillance for cancer cells due to lack of sex steroids, and increased attention from Clinical Theriogenology • Volume 9, Number 2 • June 2017 170 owners who have already had their dogs spayed or castrated.48,53 The authors are unaware of any published research documenting these phenomena. Testicular neoplasia Reported incidence of testicular neoplasia in dogs is 0.9%, with increasing age a reported risk factor.54 Castration early in life obviously is protective in all cases and castration at the time of diagnosis is reported to be curative in the majority of cases.25 Obesity Reported incidence of obesity varies from 21.4-44.4%.55-58 Some studies report higher incidence in females than in males and a breed predisposition is described.55-57 Other factors reported to be associated with obesity in dogs include housing, increasing age, and ownership by an overweight person or a person ≥ 40 years old.56,57,59-61 Although many studies report percent of a population of dogs that is reported to be obese, either by veterinarians or by pet owners, only three studies with veterinarian determined body condition have been published specifically addressing the association between gonadectomy and obesity, with all three studies showing increased incidence with gonadectomy (Table 9). Risk for development of obesity after neutering was reported to be greatest for the first two years after surgery, with no difference in likelihood of becoming obese when comparing neutered to intact dogs over ten0 years.62 The cause-and-effect relationship between gonadectomy and obesity has not been defined in dogs. In cats, decline in metabolic rate after gonadectomy has been demonstrated.63,64 Estrogen has been reported to effect satiety in women, perhaps through modulation of cholecystokinin.65 Studies disagree regarding effect of estrogen on satiety in dogs. In a study comparing dogs gonadectomized at seven weeks of age or seven months of age, or left intact, the dogs showed no difference in food intake or depth of back fat at 15 months of age.66 In other studies, spayed female dogs have been demonstrated to have an increase in food intake and increase in indiscriminate appetite after spaying compared with sham- operated or age-matched control dogs.67,68 Testosterone may effect satiety in men through secretion of gastric ghrelin.69 Castration was associated with increased appetite and subsequent weight gain in one study in dogs.70 Cranial cruciate ligament injury The incidence of cranial cruciate ligament injury was reported to be 0.6-3.5%.71-74 The disorder may or may not be more common in females than in males and is more prevalent in some breeds.71-77 Other factors reported to be positively associated with incidence of cranial cruciate ligament injury are age and weight, as well as obesity.73,74,76,78 Association of cranial cruciate ligament with conformation of the pelvic limb and with exercise are controversial, with conflicting reports in the literature.79 There are ten studies evaluating the effect of gonadectomy on incidence of cranial cruciate ligament injury, with nine showing increased incidence with gonadectomy (Table 10). Some factors may be confounded; in one study, intact dogs that developed cranial cruciate ligament injury did so at a younger age than did neutered dogs.77 Several studies have reported raw data showing numbers of affected spayed females, intact females, castrated males, and intact males with cranial cruciate ligament injury in specific breeds using data drawn from records of a referral hospital, with varying amounts of statistical analysis.23,47-49 Concerns are as described for hemangiosarcoma. In another study, it was suggested that incidence in neutered dogs was artificially elevated because owners who had paid to have their dog spayed or castrated were perhaps more attentive or more willing to bring their dog in for orthopedic treatment.72 The cause-and-effect relationship between gonadectomy and cranial cruciate ligament injury has not been defined. Because cranial cruciate ligament injury occurs more commonly in women than in men with incidence associated with phases of the menstrual cycle, it may be that hormonal changes alter the properties or function of the ligament.71,80 Closure of the growth plate in long bones may or may not be delayed if dogs undergo gonadectomy prior to puberty. A study evaluating long bone length up to six Clinical Theriogenology • Volume 9, Number 2 • June 2017171 months of age after ovariohysterectomy failed to show statistical significance between groups, while a study evaluating long bone length at 15 months of age did demonstrate such a difference.66,81 It has been hypothesized that delayed closure of growth plates may be associated with variation in length of long bones and subsequent misalignment of joints. Specific attention has been paid to possible delay in closure of femoral physes compared to tibial physes, such that there is relative overgrowth of the femur and accentuation of the tibial plateau angle. Several studies have refuted the connection of degree of the tibial plateau angle and incidence of cranial cruciate ligament injury.82-84 The authors are unaware of any published research documenting development of cranial cruciate ligament injury due to asynchrony of long bone growth and subsequent anatomic abnormalities of the stifle. Patellar luxation Reported incidence of patellar luxation was 1.3% in one study.85 Patellar luxation is a hereditary disorder that is equally prevalent in males and females and is reported to be more prevalent in some breeds.85,86 Incidence is reported to be positively correlated with age and body weight.85,86 There are three studies describing a possible link between gonadectomy and patellar luxation; two showed an increased incidence with spay or castration (Table 11). One study sampled dogs from 119 clinics across England, which minimizes the bias that may be present in studies performed at single locations.85 However, there may be differences in the breed genetics of dogs from different countries that could influence the generalizability of results. The cause-and-effect relationship between gonadectomy and patellar luxation has not been defined. Age may be a confounding factor, as increased age, which also was shown to be correlated with increased incidence of patellar luxation, may be associated with increasing laxity of the stifle joint.86 The association with increased body weight in these studies was not a reflection of increased incidence in obese dogs but rather an increased incidence in dogs with higher than average adult bodyweight for their breed and sex.85 The authors of one of these studies concluded that the available data was insufficient to permit any deductions about effect of removal of sex hormones on development of patellar luxation.86 Hip dysplasia Reported incidence of hip dysplasia is 1.7-3.5%.72,87 This is a hereditary condition that is equally prevalent in males and females and is more prevalent in some breeds.72,87 Environmental influences, including diet, exercise, and housing, also play a role in clinical manifestations of the disorder.88-92 Effect of gonadectomy on incidence of hip dysplasia is well described in six studies. Incidence was increased with gonadectomy in five of those studies; no change in incidence in at least one sex was noted in three studies (Table 12). Several published studies described incidence relative to gonadectomy in specific breeds, automatically making the data less valuable for wide extrapolation due to the hereditary component of this disorder.23,47,49,93 In addition, these studies did not include any genetic analysis of dogs in the study so the influence on genetics even within the breed could not be evaluated. In one study, incidence of hip dysplasia was reported to be higher in dogs neutered before 5.5 months of age but dogs neutered early that developed hip dysplasia were less likely to be euthanized for it than dogs neutered between six and 12 months, suggesting variation in clinical manifestation of the disorder as well as possible owner preferences for various treatment options.58 It was not clear in that study whether or not all dogs defined as having hip dysplasia had been diagnosed with the disorder by a veterinarian.58 Similarly, it is not clear in all studies at what age hip dysplasia was diagnosed, if dogs were presented for routine screening or were clinical for hip dysplasia, and if the diagnosis was made by a private practitioner or a specialist, or verified by the Orthopedic Foundation for Animals or other external reviewer. Several studies have reported raw data showing numbers of affected spayed females, intact females, castrated males, and intact males with canine hip dysplasia in specific breeds using data drawn from records of a referral hospital, with varying amounts of statistical analysis.23,47,49 Concerns are as described for hemangiosarcoma. The cause-and-effect relationship between gonadectomy and canine hip dysplasia has not been defined. As with cranial cruciate ligament injury, it has been hypothesized that delayed closure of growth Clinical Theriogenology • Volume 9, Number 2 • June 2017 172 plates may be associated with variation in length of long bones and subsequent misalignment of joints. The authors are unaware of any published research documenting misalignment of joints. Benign prostatic hypertrophy/hyperplasia Benign prostatic hypertrophy/hyperplasia (BPH) is very common in middle-aged to older dogs, with reported incidence of 50% by 2.4 years of age and 75-80% by six years of age.94-96 Development is androgen-dependent so castration early in life is protective in all cases. Surgical castration at the time of diagnosis is curative.97 Castration also is reported to increase effectiveness of treatment and long-term resolution of bacterial prostatitis in dogs, most likely through resolution of underlying BPH.98 Pyometra Incidence of pyometra in bitches increases with age, with reported incidence of 24-25% by ten years of age.99 Ovariohysterectomy early in life obviously is protective in all cases. Reported mortality associated with ovariohysterectomy at the time of diagnosis is 0-17%.100,141 Urinary incontinence Urethral sphincter mechanism incompetence, formerly known as estrogen-responsive urinary incontinence, is reported to occur in 4.9-20.0% of spayed dogs.58,101-105 The disorder has been reported to be more common in some breeds.103,106 Other factors reported to be associated with increasing incidence include increasing age and body weight, and tail docking.103,105-107 There are ten studies specifically documenting the association between gonadectomy and urethral sphincter mechanism incompetence, with all four showing increased incidence with spaying (Table 13). Incidence may vary with age or physiologic status; studies have demonstrated increased incidence when bitches were spayed at fewer than three to five months, greater than six months, or before their first estrus.23,58,104,108, 142-144 Others have refuted any connection between incidence and age at time of spaying.105 A systematic review was performed to evaluate this topic. As with mammary neoplasia, the veterinary literature is not deep enough to permit this type of analysis and the authors were forced to conclude that currently available data is insufficient for determination of the effect of neutering on the risk of urinary incontinence.109 The cause-and-effect relationship between urethral sphincter mechanism incompetence and gonadectomy has not been defined. It has been demonstrated that maximum urethral closure pressure and functional urethral length are decreased after spaying.110 Serum concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary are persistently elevated after spaying, most likely due to lack of negative feedback to the hypothalamus and pituitary from the ovaries.111 Elevated concentration of serum FSH has been associated with incontinence but effect to changes in gonadotropin concentration on changes in urethral closure pressure and subsequent incontinence are not clear.111,112, 144 Urolithiasis – calcium oxalate and struvite Prevalence of first time calcium oxalate urolithiasis in one study was reported to be 0.01%.113 Incidence of struvite urolithiasis was reported to be 0.004%.114 Calcium oxalate urolithiasis is reported to be more common in males than in females and to be more common in smaller breeds of dog.113,115,116 Struvite urolithiasis is reported to be more common in females than in males and to be more common in small breeds.114,116 In one study, calcium oxalate urolithiasis was reported to be more common than struvite urolithiasis in males, older dogs, and smaller breed dogs.117 Association between urolithiasis and gonadectomy has been reported in four studies, three of which showed increased incidence in gonadectomized dogs (Table 14). Incidence of calcium oxalate urolithiasis is reported to be increased after castration in males and incidence of struvite urolithiasis is reported to be increased after spaying in females.114,117 Again, it is possible that owners who have had their dogs gonadectomized are more observant and/or more willing to seek veterinary care and treatment. The cause-and-effect relationship between urolithiasis and gonadectomy has not been defined. Clinical Theriogenology • Volume 9, Number 2 • June 2017173 Diabetes mellitus Reported incidence of diabetes mellitus in dogs is 0.5-0.6%.118,119 It has been reported to occur more commonly in females than in males and a higher prevalence is reported in some breeds.119,120 Other factors associated with increased incidence of diabetes mellitus are increasing age and obesity.119,121,122 There are four studies evaluating the possible connection between gonadectomy and incidence of diabetes mellitus (Table 15). Two studies showed no change for females but an increased risk for diabetes mellitus in castrated males.119,121 One study showed no change in either gender.58 The most likely cause- and-effect relationships between gonadectomy and diabetes mellitus are through effect of progestogens in insulin resistance and increased likelihood of spayed or castrated dogs being obese.119,121,122,146 Chronic kidney disease Prevalence of chronic kidney disease in the single study evaluating association with gonadectomy was 0.37%.123 Incidence is increased with increasing age and some breeds are at increased risk. Gonadectomy was associated with increased incidence in one of two studies (Table 16). This study sampled 107,214 dogs from 89 clinics across England, which minimizes the bias that may be present in studies performed at single locations.123 The cause-and-effect relationship between chronic kidney disease and gonadectomy has not been defined. Atopic dermatitis Incidence of atopic dermatitis is 1.7%.124 Factors associated with incidence include age, breed, sex, and geographical location.124 There are only three studies documenting the association between gonadectomy and atopic dermatitis, with two showing increased incidence and one showing no association (Table 17).58,124,125 All studies evaluated large populations of dogs, with one describing 90,090 dogs seen at a referral hospital, one describing 22,280 dogs seen at a corporate practice, and the third describing 1842 dogs adopted from a humane organization. The first and largest of these studies also demonstrated that gonadectomized dogs were more likely to be diagnosed with other autoimmune disorders, including autoimmune hemolytic anemia (OR 1.67±0.28 in females, 1.76±0.31 in males), hypoadrenocorticism (OR 1.49±0.32 in females, 2.07±0.54 in males), hypothyroidism (OR 3.03±0.39 in females, 1.29±0.11 in males), immune-mediated thrombocytopenia (OR 3.14±0.73 in females, 2.05±0.42 in males), inflammatory bowel disease (OR 2.2±0.54 in females, 1.43±0.23 in males) and lupus erythematosus (systemic and discoid, OR 2.64±1.24 in females, not significant in males).125 The cause- and-effect relationship between autoimmune disorders, including atopic dermatitis, and gonadectomy has not been defined. Idiopathic epilepsy/cluster seizures Incidence of idiopathic epilepsy is reported to be 0.6%.126 One study reported increased incidence in male dogs and some breeds are at increased risk.126,127 There are three studies evaluating association between gonadectomy and idiopathic epilepsy (Table 18). Two studies showed increased incidence in spayed or castrated dogs and one study showed no change in incidence with gonadectomy.126- 128 Regarding cluster seizures, intact males were reported to be more likely to have cluster seizures than neutered males and intact females had cluster seizures with greater frequency than did spayed females.128 The cause-and-effect relationship between idiopathic epilepsy and gonadectomy has not been defined. One study suggested that hormones may play a role, perhaps by having an excitatory effect, but the infrequent cycling of female dogs would argue against an effect of such a stimulus throughout the normal prolonged anestrus.128 One author suggested that any association between gonadectomy and idiopathic epilepsy may be artefactual if owners of dogs with epilepsy present their dogs for gonadectomy as a way of managing their seizures or to prevent them from reproducing.127 Clinical Theriogenology • Volume 9, Number 2 • June 2017 174 Lifespan Gonadectomy has been associated with increased lifespan in most studies where this was evaluated (Table 19). Spayed dogs have been reported to live 23.0-26.3% longer than intact bitches and castrated males have been reported to live 13.8-18.0% longer than intact males.129-133 Therefore, any health problem that tends to occur in older dogs could be more common in gonadectomized animals than in intact animals, simply because gonadectomized animals may live long enough to develop the health problem. Suggested reasons for this increased longevity include increased attention from owners of dogs they have had neutered, and changes in behavior, for example decreased roaming for breeding purposes, which minimize risks to the animal. The latter hypothesis is supported by data demonstrating that neutered dogs were less likely to die of infectious disease or trauma and were more likely to die of cancer and immune-mediated disease.130 One study evaluating a group of exceptionally long-live bitches of one breed demonstrated increased lifespan associated with increased ovary exposure over their lifetime, suggesting benefit of exposure to compounds secreted directly from the ovary or compounds for which synthesis or secretion is modulated by the ovary.134 An example of one such compound is LH, for which concentrations are persistently elevated after ovariectomy and for which many tissues have receptors.135 Interpretation and explanation of data When reading any scientific study, the reader is recommended to ask questions to help them interpret the data. Suggested concerns include: What kind of study was performed? Ideally, to study causation, the animals should be newly diagnosed with the disease of interest (incident cases). Studies that identify animals for inclusion based on the outcome (the health problem rather than on gonadectomy) are more prone to bias than those studies which sample based on gonadectomy status or age. Studies sampling on the outcome may include errors from missing records and the need for dog owners and veterinarians to rely on memory.50 For these reasons, studies that do not rely on historical data or memory (prospective studies) generally are considered to generate more accurate information. A study where the dogs were randomly assigned to age of gonadectomy (clinical trial) would be the best design to decrease bias. However, such studies are rare and expensive. Other studies that do not sample based on outcome and are prospective are the next best option (cohort designs). For all studies, the choice of controls is crucial for an unbiased study. A control for studies which select dogs based on the outcome (case control study) is an individual selected in an unbiased manner from those individuals who would have been included in the case series had they developed the disorder under study.136 Sampling for controls within a referral hospital is plagued with the problems described above but sampling for controls in the general population outside of the referral hospital also may introduce error. Those dogs never would have been in the case series precisely because they would not have been presented to the referral hospital. For these reasons and others, studies including dogs evaluated at a large number of private veterinary hospitals across a geographic region may be of great value and be less prone to bias. From what population was the sample drawn? Very small samples may not be representative of the population.8 Very small sample size may also not permit the investigator to demonstrate an effect statistically even if an effect is truly present.8 Very large studies may show statistical significance of a very small difference between groups that is not large enough to be relevant scientifically or biologically. As previously mentioned, samples drawn from referral hospitals, including veterinary teaching hospitals, may not be an accurate reflection of the larger population. Samples collected by evaluation of dog breeders also may not be reflective of the large dog-owning public as dog breeders often have a different level of knowledge and different goals for their animals compared to pet owners.50 How do we know what the statistics are telling us? Statistically significant results can be due to errors in the study design or in the interpretation of the results. In addition, statistical significance is only one criterion for determining a cause-and-effect sequence. The lack of a defined cause-and-effect for gonadectomy and many of the disorders described is troubling for this reason. When looking at odds or hazard ratios or relative risks which provide an estimate of the magnitude of the risk, always consider whether the range includes unity; if so, the author is stating that there is a statistical chance that incidence Clinical Theriogenology • Volume 9, Number 2 • June 2017175 in neutered animals is equivalent to incidence in intact animals. For that reason, the range of an odds ratio or similar statistical construct is more valid to assess than is any single value, including a p value. In addition, when applying these results to a clinical situation, consider the actual incidence of the problem. If the problem is very rare, even a large relative risk from a good study does not mean that the problem is a major concern. Another consideration with statistical analysis and publications, especially when performing systematic analyses is the “file drawer problem”, or lack of publication of negative data. A few of the studies described above did include negative data, which helps create a more balanced overall picture. Finally, when looking at the statistical analysis, readers should be cautious not to draw conclusions solely on the apparent complexity of the analysis. Simple statistics may be superior to very complex statistics, which sometimes reveal mathematically valid evidence for statistical significance that is not supported scientifically. Conversely, more complex statistics may be necessary to evaluate confounding factors within a study, for example the association between gonadectomy and any disorder to which animals are predisposed by increasing age, sex, heredity, or other factors.8 Statistical significance demonstrating associations is only one small piece of evidence for causation. Sir Austin Bradford Hill established in 1965 what have become known as Hill’s Criteria of Causation (Table 20). These provide a framework to help the reader understand the complexities of determining causation. They also put into context data that is statistically significant but may not make an obvious contribution to demonstrating causation. Veterinarians are strongly encouraged to read manuscripts completely, not just to read the abstract or short summaries of studies, and to consider criteria such as these when evaluating information. One of the authors (MVRK) used data from a veterinary teaching hospital to try to illustrate the above points. For one calendar year, information was gathered regarding how many unique spayed female, intact female, castrated male, and intact male dogs were seen overall and how many dogs in each category were diagnosed with a variety of disorders, as coded in the electronic medical record, a cross- sectional study (Table 21). Two-way contingency table analysis was performed. As is obvious from the table, very few of the disorders described in this paper were supported by data from this unique population. Specific errors that arose in this small study were lack of data due to inadequate completion of medical records by clinicians and subsequent lack of coded data; low number of animals admitted to the referral hospital for common conditions such as mammary neoplasia; and lack of consideration for confounding factors where appropriate. Some examples demonstrate finding of p values that are misleading when looking at the single odds ratio estimate. For example, the odds ratio for transitional cell carcinoma is 4.1; this is a rather large odds ratio (far from unity). However, the p value is not significant and the range for the odds ratio includes unity, due in part to a small sample size. If only the single value for the odds ratio had been provided, a high risk if gonadectomized would appear to be present using these data. Without the p value or confidence interval, statistical significance cannot be determined. For osteosarcoma, the p value is just significant (near the cutoff of 0.05) but the range for the odds ratio just includes unity. If only the single p value or the single value for the odds ratio had been provided, a significant risk would appear to exist that is not clearly supported if all the data are presented. These data demonstrate the value of confidence intervals and how they can be used to identify significant risk when single values are near the cutoff point. It is not uncommon for practicing veterinarians to contact one of the authors and ask for a one- sentence response to their question of the best age at which to spay or castrate dogs. There is no appropriate simple response as there is a great amount of information available, all of which will be assessed slightly differently by each person reading those studies, and non-medical considerations must be taken into account, including population control, effects of gonadectomy on behavior, and the wishes of and ability to provide care by the owner or guardian of the dog. General recommendations are the following: For populations of unowned dogs, for example at humane organizations, population control concerns outweigh concerns about individual animals. Animals that leave the humane organization intact Clinical Theriogenology • Volume 9, Number 2 • June 2017 176 may repopulate that shelter with their offspring, and may well be returned to the shelter themselves, as it has been demonstrated that being intact is a risk factor for surrender.137 For animals with a responsible owner or guardian, veterinarians need to develop a means of communicating this large amount of contradictory data. One way to help clients think through the information is to provide them with an idea of the varying impacts of the disorders the veterinarian believes to be associated with gonadectomy. In one example of this method, veterinarians generated a morbidity score for various disorders that was multiplied by incidence of those disorders to create an impact score (Table 22).138 Positive impact scores were associated with better health after gonadectomy and negative impact scores with worse health after gonadectomy. For female dogs, benefits of ovariohysterectomy outweighed detriments and prepubertal spay was recommended; for male dogs, benefits of castration did not outweigh detriments until the animal was likely to develop age-related, benign diseases of the reproductive tract, or about 2.5 years of age.138 Use of this kind of tool also gives veterinarians an opportunity to talk with clients about other topics in preventive medicine. For example, this provided a very real way to demonstrate to clients the concerns associated with obesity, which had a high impact score in both females and males.138 Another technique would be to provide clients with some idea of positives and negatives for their specific animal. This requires specific knowledge of predispositions due to age, breed, and other factors for all of the disorders described. An example previously described is the following:4 You are a veterinarian speaking to the owner of an eight-week-old female Labrador Retriever that is not intended for breeding. This dog would benefit greatly from spaying before her first estrus as a means of preventing mammary gland tumors, which are extremely common relative to other diseases of concern and cause substantial morbidity. Because of her breed, reported detriments of spaying include an increased predisposition to cranial cruciate ligament injury, hemangiosarcoma, and obesity. However, there is a low incidence of hemangiosarcoma, and obesity can be readily controlled with diet and exercise, which leaves cranial cruciate ligament injury as the most important possible detriment. Because the incidence of cranial cruciate ligament rupture is lower than that of mammary gland neoplasia, you choose to recommend spaying and educate the owner about maintenance of optimal body condition and other management techniques that will minimize potential for cranial cruciate ligament injury. The best age at which to perform the spay must include considerations of when the dog’s first estrus is likely to occur and how young one can spay a dog before greatly increasing risk of urethral sphincter mechanism incompetence. The likely recommendation for this bitch would be ovariohysterectomy at about five to six months of age. All of these methods rely on the veterinarian having taken the time to assess the information available and to use their knowledge of the subject to educate clients as they collaborate on the best decision for a specific individual animal. Research on this topic surely will continue and hopefully will include more information about effect of neuter at various ages on these disorders and a greater elucidation of cause-and-effect. Acknowledgements The authors wish to think Laurel Schedin and Tina Roeser for data collection. References 1. Trevejo R, Yang M, Lund EM: Epidemiology of surgical castration of dogs and cats in the United States. J Am Vet Med Assoc 2011;238:898-904. 2. Association of Shelter Veterinarians: Available at: . 3. Root Kustritz MV: Effects of surgical sterilization on canine and feline health and on society. Reprod Domest Anim 2012;47(Suppl 4):214-222. 4. Root Kustritz MV: Determining the optimal age for gonadectomy of dogs and cats. J Am Vet Med Assoc 2007;231:1665-1675. 5. Romagnoli S: Surgical gonadectomy in the bitch and queen: should it be done and at what age? Available at : . Clinical Theriogenology • Volume 9, Number 2 • June 2017177 6. 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Sundburg CR, Belanger JM, Bannasch DL, et al: Gonadectomy effects on the risk of immune disorders in the dog: a retrospective study. BMC Vet Res 2016;12:278-287. 126. Kearsley-Fleet L, O’Neill DG, Volk HA, et al: Prevalence and risk factors for canine epilepsy of unknown origin in the UK. Vet Rec 2013;172:338-342. 127. Short AD, Dunne A, Lohi H, et al: Characteristics of epileptic episodes in UK dog breeds: an epidemiological approach. Vet Rec 2011;169:48-51. 128. Monteiro R, Adams V, Keys D, et al: Canine idiopathic epilepsy: prevalence, risk factors and outcome associated with cluster seizures and status epilepticus. J Small Anim Pract 2012;53:526-530. 129. Banfield State of Pet Health 2013 Report: Available at: . 130. Hoffman JM, Creevy KE, Promislow DE: Reproductive capability is associated with lifespan and cause of death in companion dogs. PLos ONE 2013;8:e61082. doi:10-1371/journal.pone.0061082. 131. Moore GE, Burkman KD, Carter MN, et al: Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993-1996). J Am Vet Med Assoc 2001;219:209-214. 132. Bronson RT: Variation in age at death of dogs of different sexes and breed. Am J Vet Res 1982;43:2057-2059. 133. Michell AR: Longevity of British breeds of dog and its relationship with sex, size, cardiovascular variables and disease. Vet Rec 1999;145:625-629. 134. Waters DJ, Kengeri SS, Clever B, et al: Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs. Aging Cell 2009;8:752-755. 135. Zwida K, Kutzler MA: Non-reproductive long-term health complications of gonad removal in dogs as well as possible causal relationships with post-gonadectomy elevated luteinizing hormone (LH) concentrations. J Etiology Anim Hlth 2016;1:1-11. Clinical Theriogenology • Volume 9, Number 2 • June 2017181 136. Kelsey JL, Moore AS, Glickman LT: Epidemiologic studies of risk factors for cancer in pet dogs. Epidemiol Rev 1998;20:204-217. 137. New JC, Salman MD, King M, et al: Characteristics of shelter-relinquished animals and their owners compared with animals and their owners in U.S. pet-owning households. J Appl Anim Welfare Sci 2000; 3:179-201. 138. Root Kustritz MV: Use of an impact score to guide client decision-making about timing of spay-castration of dogs and cats. Clin Therio 2012;4:481-485. 139. Duerr FM, Duncan CG, Savicky RS, et al: Risk factors for excessive tibial plateau angle in large-breed dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2007;231:1688-1691. 140. Gruntzig K, Graf R, Boo G, et al: Swiss canine cancer registry 1955-2008: Occurrence of the most common tumour diagnoses and influence of age, breed, body size, sex and neutering status on tumour development. J Comp Pathol 2016;155:156-170. 141. Jitpean S, Strom-Holst B, Emanuelson U, et al: Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases. BMC Vet Res 2014;10:6-17. 142. Byron JK, Taylor KJ, Phillips GS, et al: Urethral sphincter mechanism incompetence in 163 neutered female dogs: diagnosis, treatment, and relationship of weight and age at neuter to development of disease. J Vet Intern Med 2017;31:442-448. 143. 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 Assoc 2013;242:959-962. 144. Reichler IM, Hung E, Jochle W, et al: FSH and LH plasma levels in bitches with differences in risk for urinary incontinence. Theriogenology 2005;63:2164-2180. 145. Marmor M, Willeberg P, Glickman LT, et al: Epizootologic patterns of diabetes mellitus in dogs. Am J Vet Res 1982;43:465-470. 146. Poppl AG, Mottin TS, Gonzalez FH: Diabetes mellitus remission after resolution of inflammatory and progesterone- related conditions in bitches. Res Vet Sci 2013;94:471-473. Clinical Theriogenology • Volume 9, Number 2 • June 2017 182 T ab le 1 . K ey c ri te ri a to c on si de r w he n re vi ew in g st ud ie s ab ou t g on ad ec to m y an d di se as e ca us at io n or p re ve nt io n B es t s tu dy d es ig n fo r ev id en ce f or c au sa tio n, w he n do ne w el l: ra nd om iz ed c lin ic al tr ia ls p ro vi de th e st ro ng es t l in k be tw ee n po te nt ia l c au se a nd p ot en tia l e ff ec t. C oh or t s tu di es a re n ex t, fo ll ow ed b y ca se -c on tr ol a nd th en c as e se ri es . E xp er t o pi ni on a nd n on -s ys te m at ic r ev ie w s pr ov id e th e w ea ke st e vi de nc e fo r ca us at io n. U nb ia se d su bj ec t s el ec tio n (h ow w er e th e do gs s el ec te d an d fr om w he re ): O ne s ou rc e of p ot en tia l b ia s is if th er e ar e m an y m is si ng d at a po in ts o r la rg e lo ss es to f ol lo w -u p. I n ad di tio n, w he th er th e do gs w er e re cr ui te d fr om p ri va te pr ac ti ce , r ef er ra l o r sp ec ia lt y ho sp it al s, b re ed c lu bs o r pa th ol og y se rv ic es c an a ls o in fl ue nc e th e di se as e di ag no si s fr eq ue nc y, s ev er it y an d ag e. D og s se en a t r ef er ra l h os pi ta ls a re n ot li ke ly to b e re pr es en ta tiv e of d og s se en in p ri va te pr ac ti ce s. F ac to rs s uc h as c os t, di st an ce to tr av el , s ev er it y of th e di se as e or c om pl ex ity o f th e tr ea tm en t, in te re st o f fa cu lty a nd a va ila bi lit y of f un di ng to p ay f or tr ea tm en t a ll in fl ue nc e w hi ch d og s ar e re fe rr ed a nd a t w ha t s ta ge o f di se as e. A de qu at e sa m pl e siz e: A la rg e en ou gh s am pl e he lp s to e ns ur e th at th e an im al s in th e st ud y re pr es en t t he a ni m al s to w ho m w e w ou ld li ke to e xt ra po la te th e re su lts . A ls o, a la rg e en ou gh s am pl e is n ee de d to b e su re th at th e st ud y ha d en ou gh a ni m al s to b e ab le to f in d a di ff er en ce s ta tis tic al ly if o ne r ea ll y ex is te d (p ow er c al cu la ti on s ca n en su re th is ). C on ve rs el y, a n ex tr em el y la rg e sa m pl e m ay id en ti fy s ta ti st ic al s ig ni fi ca nc e th at is m at he m at ic al in n at ur e an d no t re fl ec tiv e of u nd er ly in g sc ie nc e. A cc ur at e an d pr ec ise m ea su re m en t o f th e ch ar ac te ri st ic s of in te re st : in th is c as e, a cc ur at e as se ss m en t o f th e ag e of g on ad ec to m y is c ri ti ca l. D at a fr om th e ve te ri na ri an p er fo rm in g th e su rg er y is li ke ly m os t a cc ur at e. O w ne r re co lle ct io n of th e da te is p ro ne to d if fi cu lty in r ec al l, pa rt ic ul ar ly f or o ld er d og s. D og s w ho w er e ac qu ir ed a s ad ul ts an d w er e al re ad y go na de ct om iz ed m ay n ot h av e a kn ow n da te o f su rg er y an d th er ef or e w ill b e sy st em at ic al ly ex cl ud ed f ro m th e da ta s et . A de qu at e co nt ro l o f c on fo un di ng fa ct or s: a li st in g th e co nf ou nd er s, w hy e ac h w as in cl ud ed a nd h ow e ac h w as ad dr es se d is c ri ti ca l. I n th is c as e, a ge , s ex , b re ed , g en et ic s, b od y co nd iti on s co re , d ie t a nd e xe rc is e m ay b e im po rt an t fo r th e di se as es o f in te re st . C au tio us a nd c ri tic al a ss es sm en t o f r es ul ts b y th e au th or s: t he re s ho ul d be a s ec tio n in th e di sc us si on a bo ut th e li m it at io ns o f th e st ud y as w el l a s th e in te rp re ta ti on o f th e re su lts in li gh t o f th e ob je ct iv es , l im ita ti on s, a na ly si s, ot he r pu bl is he d w or k an d ot he r re le va nt e vi de nc e th at h ig hl ig ht s th e st re ng th s an d w ea kn es se s of th e cu rr en t s tu dy .       Clinical Theriogenology • Volume 9, Number 2 • June 2017183 T ab le 2 . L it er at ur e re vi ew – m am m ar y ne op la si a R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S FO R C O N FO U N D IN G F A C T O R S 17 D ec re as ed N eu te re d bi tc he s 1/ 3 as li ke ly a s in ta ct bi tc he s to de ve lo p co nd iti on C as e- co nt ro l st ud y D ia gn os ti c la bo ra to ry su bm is si on s 20 75 tu m or s N ot a va ila bl e in a ll m ed ic al r ec or ds ac ce ss ed A ge -m at ch ed c on tr ol s, br ee d va ri at io n id en tif ie d in st ud y bu t n ot in co rp or at ed in to s ta tis tic al a na ly si s 20 D ec re as ed O R 0 .0 1 if sp ay ed b ef or e 1 ye ar o f ag e, 0 .1 1 if s pa ye d 1- 2. 5 ye ar s of a ge C as e- co nt ro l st ud y D ia gn os ti c la bo ra to ry su bm is si on s 15 0 af fe ct ed do gs O w ne r qu es tio nn ai re C on tr ol s m at ch ed f or a ge (n = 14 7) a nd s iz e (n = 13 1) ; ob es ity a nd h ig h fa t d ie t w er e in cl ud ed in s ta tis tic al an al ys is 18 D ec re as ed p< 0. 00 01 C as e- c on tr ol st ud y P at ie nt s ad m it te d to pr iv at e pr ac ti ce s an d sh ar ed w it h a ca nc er r eg is tr y 57 6 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s C on tr ol s (n = 14 55 ) an d hi st or y of p ro ge st in tr ea tm en t, ag e w er e ev al ua te d se pa ra te ly 19 D ec re as ed 2X g re at er in ci de nc e in in ta ct f em al es , p< 0. 00 01 C as e- co nt ro l st ud y C an ce r re gi st ry su bm is si on s -- - N ot c on si de re d C on tr ol s fr om p ri va te pr ac ti ce s, a ge , s ex a nd br ee d in cl ud ed in s ta ti st ic al an al ys is 58 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy A ni m al s ad op te d fr om hu m an e or ga ni za tio n 18 42 d og s O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in s ta tis tic al an al ys is , l ow n um be r of af fe ct ed a ni m al s m ay h av e Clinical Theriogenology • Volume 9, Number 2 • June 2017 184 de cr ea se d st at is ti ca l p ow er 23 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 70 5 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , b re ed - sp ec if ic s tu dy ( G er m an sh ep he rd d og s) , s ex in cl ud ed in s ta tis ti ca l an al ys is 14 0 D ec re as ed O R 0 .4 ( ex v iv o or p os t- m or te m sa m pl es ) or 0 .6 (p os t- m or te m sa m pl es ) co m pa re d to O R = 1 fo r in ta ct fe m al es R et ro sp ec ti ve st ud y C an ce r re gi st ry su bm is si on s E xa ct nu m be r of tu m or s in fe m al e do gs n ot pr ov id ed N ot c on si de re d S ex a nd a ge in cl ud ed in st at is ti ca l a na ly si s. T um or ty pe s no t a lw ay s se pa ra te d by a na to m ic lo ca tio n. Clinical Theriogenology • Volume 9, Number 2 • June 2017185 T ab le 3 . L it er at ur e re vi ew – p ro st at ic n eo pl as ia R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 33 In cr ea se d O R 3 .9 ( 2. 3- 6. 8) C as e- co nt ro l st ud y D ia gn os ti c la bo ra to ry su bm is si on s 70 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, n ec ro ps y re po rt s, o w ne r / D V M qu es tio nn ai re /in te rv ie w , ju st g on ad ec to m iz ed ye s or n o A ge -m at ch ed c on tr ol s 28 In cr ea se d O R 4 .3 ( 2. 5- 7. 6) C as e co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 56 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, o w ne r in te rv ie w , j us t go na de ct om iz ed y es o r no B re ed v ar ia tio n id en tif ie d in s tu dy b ut n ot in co rp or at ed in to st at is ti ca l a na ly si s 29 In cr ea se d O R 2 .4 ( 1. 0- 9. 6) C as e se ri es P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 31 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es o r no N o co nt ro ls 30 In cr ea se d O R 2 .8 ( 2. 6- 3. 1) C as e- co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 68 1 af fe ct ed do gs N ot a va ila bl e th ro ug h re gi st ry ; j us t go na de ct om iz ed y es o r no A ge -m at ch ed c on tr ol s, br ee d in cl ud ed in s ep ar at e an al ys is 32 U nc ha ng ed -- -- C as e se ri es P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 43 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s N o co nt ro ls , s m al l s am pl e si ze O R = o dd s ra ti o Clinical Theriogenology • Volume 9, Number 2 • June 2017 186 T ab le 4 . L it er at ur e re vi ew – tr an si ti on al c el l c ar ci no m a R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S FO R C O N FO U N D IN G F A C T O R S 37 In cr ea se d O R 4 .4 ( 1. 4- 13 .8 ) C as e- co nt ro l st ud y S co tti sh te rr ie rs re cr ui te d th ro ug h sp ec ia lt y/ re fe rr al ho sp ita l, br ee d cl ub 83 af fe ct ed do gs O w ne r qu es tio nn ai re A ge -m at ch ed c on tr ol s, br ee d- sp ec if ic s tu dy 39 In cr ea se d O R 2 .0 ( no C I re po rt ed ), p= 0. 03 C as e- co nt ro l st ud y D ia gn os ti c la bo ra to ry su bm is si on s 11 5 tu m or s R ev ie w o f ho sp ita l re co rd s C on tr ol p op ul at io n fr om sp ec ia lt y/ re fe rr al h os pi ta l, ag e, b re ed , g en de r, w ei gh t w er e an al yz ed s ep ar at el y O R = o dd s ra ti o Clinical Theriogenology • Volume 9, Number 2 • June 2017187 T ab le 5 . L it er at ur e re vi ew – o st eo sa rc om a R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 42 In cr ea se d R R 3 .8 ( 1. 5- 9. 2) f em al es ; R R 3 .1 ( 1. 1- 8. 3) m al es R et ro sp ec ti ve co ho rt s tu dy R ec ru it ed th ro ug h br ee d cl ub s 86 a ff ec te d do gs , 59 7c on tr ol s w ith ou t co nd iti on , O w ne r qu es tio nn ai re /in te rv ie w fo r ag e at g on ad ec to m y 59 7c on tr ol s w ith ou t c on di tio n, br ee d- sp ec if ic st ud y (R ot tw ei le r) , he ig ht , w ei gh t in cl ud ed in st at is ti ca l a na ly si s 23 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 46 5 m al e do gs , 7 05 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , br ee d- sp ec if ic st ud y (G er m an sh ep he rd d og s) , se x in cl ud ed in st at is ti ca l a na ly si s 14 0 In cr ea se d O R 1 .6 ( ex vi vo o r ne cr op sy sa m pl es ) or 2 .0 (n ec ro ps y sa m pl es ) co m pa re d to O R = 1 fo r in ta ct m al es , no s ig ni fi ca nt ef fe ct in fe m al es R et ro sp ec ti ve st ud y C an ce r re gi st ry su bm is si on s E xa ct nu m be r of tu m or s in m al e do gs no t pr ov id ed N ot c on si de re d S ex a nd a ge in cl ud ed in st at is ti ca l a na ly si s. R R = r el at iv e ri sk Clinical Theriogenology • Volume 9, Number 2 • June 2017 188 T ab le 6 . L it er at ur e re vi ew – h em an gi os ar co m a R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 45 In cr ea se d (f em al es ) O R 2 .2 ( 1. 2- 4. 1) C as e- co nt ro l st ud y D ia gn os ti c la bo ra to ry su bm is si on s 59 af fe ct ed do gs D V M q ue st io nn ai re , ju st g on ad ec to m iz ed ye s or n o R an do m s am pl e of bi op sy s ub m is si on s , a ge in cl ud ed in s ta tis ti ca l an al ys is 43 In cr ea se d R R 5 .3 ( 4. 0- 7. 2) fe m al es ; 1 .6 ti m es m or e lik el y if ca st ra te d C as e co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 63 3 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es o r no S ex , b re ed a nd y ea r of di ag no si s w er e ev al ua te d se pa ra te ly 47 In cr ea se d (f em al es ); U nc ha ng ed ( m al es ) R R 6 .1 ( 1. 2- 31 .4 ) fo r fe m al es s pa ye d af te r 1 ye ar o f ag e R et ro sp ec ti ve co ho rt s tu dy G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 36 4 fe m al e do gs , 3 95 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n re tr ie ve rs ), s ex w as in cl ud ed in s ta ti st ic al an al ys is , a ge w as an al yz ed s ep ar at el y 23 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 46 5 m al e do gs , 7 05 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , b re ed - sp ec if ic s tu dy ( G er m an sh ep he rd d og s) , s ex in cl ud ed in s ta tis ti ca l an al ys is 49 U nc ha ng ed -- -- R et ro sp ec tiv e co ho rt s tu dy L ab ra do r an d G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 11 47 fe m al e do gs , 14 35 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n an d L ab ra do r re tr ie ve rs ), s ex w as in cl ud ed in s ta tis ti ca l an al ys is Clinical Theriogenology • Volume 9, Number 2 • June 2017189 48 In cr ea se d (f em al es ); U nc ha ng ed ( m al es ) O R 9 .0 ( 2. 8- 29 .4 ) R et ro sp ec ti ve co ho rt s tu dy V iz sl as r ec ru ite d th ro ug h br ee d cl ub s 25 05 do gs O w ne r qu es ti on na ir e B re ed -s pe ci fi c st ud y (v iz sl as ), s ex w as in cl ud ed in s ta tis ti ca l an al ys is 14 0 In cr ea se d O R 1 .6 ( ex v iv o or p os t- m or te m sa m pl es ) or 2 .4 (p os t- m or te m sa m pl es ) co m pa re d to O R = 1 fo r in ta ct fe m al es R et ro sp ec ti ve st ud y C an ce r re gi st ry su bm is si on s E xa ct nu m be r of tu m or s in f em al e do gs n ot pr ov id ed N ot c on si de re d S ex a nd a ge in cl ud ed in st at is ti ca l a na ly si s. T um or ty pe s no t a lw ay s se pa ra te d by a na to m ic lo ca tio n. O R = o dd s ra ti o, R R = r el at iv e ri sk Clinical Theriogenology • Volume 9, Number 2 • June 2017 190 T ab le 7 . L it er at ur e re vi ew – ly m ph os ar co m a R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 51 In cr ea se d (f em al es ) O R 1 .5 ( 1. 4- 1. 6) G ol de n an d L ab ra do r re tr ie ve rs , G er m an sh ep he rd s an d bo xe rs w er e at in cr ea se d ri sk C as e- co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 14 ,5 73 do gs R ev ie w o f re gi st ry re co rd s, go na de ct om iz ed y es or n o A ge - an d br ee d- m at ch ed co nt ro ls f ro m r eg is tr y, al so s ex , b re ed a nd a ge w er e in cl ud ed in st at is ti ca l a na ly si s 47 U nc ha ng ed (f em al es ); In cr ea se d (m al es ) p< 0. 05 f or m al es c as tr at ed ea rl y R et ro sp ec ti ve co ho rt s tu dy G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 36 4 fe m al e do gs , 3 95 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n re tr ie ve rs ), s ex w as in cl ud ed in st at is ti ca l a na ly si s, a ge w as a na ly ze d se pa ra te ly 23 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 46 5 m al e do gs , 7 05 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , br ee d- sp ec if ic s tu dy (G er m an s he ph er d do gs ), s ex in cl ud ed in st at is ti ca l a na ly si s 49 In cr ea se d (f em al e G ol de ns ); In cr ea se d (m al e G ol de ns ); U nc ha ng ed ( L ab s) p= 0. 01 f or fe m al es s pa ye d fr om 6 -1 1 m on th s of a ge ; p= 0. 00 7 fo r m al es c as tr at ed fr om 6 -1 1 R et ro sp ec ti ve co ho rt s tu dy L ab ra do r an d G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 11 47 fe m al e do gs , 14 35 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n an d L ab ra do r re tr ie ve rs ), s ex w as in cl ud ed in s ta tis ti ca l an al ys is , a ge w as an al yz ed s ep ar at el y Clinical Theriogenology • Volume 9, Number 2 • June 2017191 m on th s of a ge 48 In cr ea se d O R 4 .3 ( 1. 9- 9. 7) R et ro sp ec ti ve co ho rt s tu dy V iz sl as r ec ru ite d th ro ug h br ee d cl ub s 25 05 do gs O w ne r qu es ti on na ir e B re ed -s pe ci fi c st ud y (v iz sl as ), s ex w as in cl ud ed in s ta tis ti ca l an al ys is 14 0 In cr ea se d O R 1 .1 ( ex v iv o or p os t- m or te m sa m pl es ) or 1 .6 (p os t- m or te m sa m pl es ) co m pa re d to O R = 1 fo r in ta ct fe m al es ; O R 1 .3 (e x vi vo o r po st -m or te m sa m pl es ) or 2 .3 (p os t- m or te m sa m pl es ) co m pa re d to O R = 1 fo r in ta ct m al es R et ro sp ec ti ve st ud y C an ce r re gi st ry su bm is si on s E xa ct nu m be r of tu m or s in f em al e ve rs us m al e do gs no t pr ov id ed N ot c on si de re d S ex a nd a ge in cl ud ed in st at is ti ca l a na ly si s. O R = o dd s ra tio Clinical Theriogenology • Volume 9, Number 2 • June 2017 192 T ab le 8 . L it er at ur e re vi ew – m as t c el l t um or R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 53 In cr ea se d (f em al es ) O R 4 .1 ( 2. 2- 7. 7) C as e- co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 25 2 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es or n o C on tr ol s fr om ho sp ita l p op ul at io n w ith ou t c on di tio n, ag e, s ex a nd b re ed w er e in cl ud ed in st at is ti ca l a na ly si s 52 U nc ha ng ed In cr ea se d O R 0 .1 ( 0. 1- 0. 2) a ll ne ut er ed co m pa re d to a ll in ta ct , n o in fl ue nc e of s ex C as e- co nt ro l st ud y R eg is tr y fr om pr iv at e pr ac ti ce su bm is si on s 45 3 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es or n o A ge , s ex , i ns ur an ce st at us , b re ed , w ei gh t an d br ee d ty pe w er e in cl ud ed in st at is ti ca l a na ly si s 47 In cr ea se d (f em al es ); U nc ha ng ed ( m al es ) C ou ld n ot co m pl et e st at is tic al an al ys is R et ro sp ec ti ve co ho rt s tu dy G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 36 4 fe m al e do gs , 3 95 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n re tr ie ve rs ), se x w as in cl ud ed in st at is ti ca l a na ly si s, ag e w as a na ly ze d se pa ra te ly 23 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 46 5 m al e do gs , 7 05 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , br ee d- sp ec if ic s tu dy (G er m an s he ph er d do gs ), s ex in cl ud ed in s ta tis tic al a na ly si s 49 In cr ea se d (f em al e G ol de ns ); U nc ha ng ed ( m al e p= 0. 01 f or fe m al es s pa ye d at 2 -8 y ea rs o f R et ro sp ec ti ve co ho rt s tu dy L ab ra do r an d G ol de n re tr ie ve rs 11 47 fe m al e do gs , R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n an d L ab ra do r re tr ie ve rs ), Clinical Theriogenology • Volume 9, Number 2 • June 2017193 G ol de ns ); U nc ha ng ed ( L ab s) ag e ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 14 35 m al e do gs se x in cl ud ed in st at is ti ca l a na ly si s, ag e w as a na ly ze d se pa ra te ly 48 In cr ea se d O R 3 .5 ( 2. 3- 5. 4) R et ro sp ec ti ve co ho rt s tu dy V iz sl as r ec ru ite d th ro ug h br ee d cl ub s 25 05 do gs O w ne r qu es ti on na ir e B re ed -s pe ci fi c st ud y (v iz sl as ), s ex w as in cl ud ed in st at is ti ca l a na ly si s, ag e w as a na ly ze d se pa ra te ly 14 0 In cr ea se d O R 1 .2 ( ex vi vo o r po st - m or te m sa m pl es ) or 3 .7 (p os t- m or te m sa m pl es ) co m pa re d to O R = 1 fo r in ta ct fe m al es ; 1 .2 (e x vi vs o or po st -m or te m sa m pl es ) or 3 .0 (p os t- m or te m sa m pl es ) co m pa re d to O R = 1 fo r in ta ct m al es R et ro sp ec ti ve st ud y C an ce r re gi st ry su bm is si on s E xa ct nu m be r of tu m or s in m al e do gs n ot pr ov id ed N ot c on si de re d S ex a nd a ge in cl ud ed in st at is ti ca l a na ly si s. O R = o dd s ra tio Clinical Theriogenology • Volume 9, Number 2 • June 2017 194 T ab le 9 . L it er at ur e re vi ew – o be si ty R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 55 In cr ea se d O R 1 .6 ( 1. 2- 2. 1) C as e- co nt ro l st ud y P at ie nt s ad m it te d to pr iv at e pr ac ti ce s in C hi na ; D V M s de te rm in ed b od y co nd iti on s co re (B C S ) 23 91 do gs O w ne r qu es tio nn ai re /in te rv ie w , ju st g on ad ec to m iz ed ye s or n o A ge , b re ed , s ex a nd m an y ot he r va ri ab le s in cl ud ed in s ta tis ti ca l an al ys is 57 In cr ea se d G on ad ec to m iz ed do gs 2 ti m es m or e lik el y to be o be se th an in ta ct d og s C ro ss se ct io na l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita ls a nd pr iv at e pr ac ti ce s in E ng la nd ; D V M s de te rm in ed B C S 82 68 do gs D V M q ue st io nn ai re , ju st g on ad ec to m iz ed ye s or n o B re ed , s ex a nd a ge w er e in cl ud e in s ta tis tic al an al ys is 62 In cr ea se d G on ad ec to m iz ed do gs ( ye s/ no ) H R ~ 2 fo r 1 to 2 ye ar s af te r go na de ct om y; no d if fe re nc e fo r ag e at go na de ct om y R et ro sp ec ti ve co ho rt s tu dy C or po ra te pr iv at e pr ac ti ce ; ho sp ita l s ta ff de te rm in ed B C S 25 99 do gs R ev ie w o f ho sp ita l re co rd s A ge -m at ch ed c on tr ol s, br ee d si ze , s ex , a nd o th er va ri ab le s in cl ud ed in st at is ti ca l a na ly si s O R = o dd s ra ti o Clinical Theriogenology • Volume 9, Number 2 • June 2017195 T ab le 1 0. L ite ra tu re r ev ie w – c ra ni al c ru ci at e li ga m en t i nj ur y R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 71 In cr ea se d O R 2 .2 ( 1. 3- 3. 8) f em al es ; O R 1 .6 ( 0. 8- 3. 0) m al es C as e- co nt ro l s tu dy P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 11 2 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es o r no B re ed , s iz e an d se x w er e in cl ud ed in st at is ti ca l a na ly si s 72 In cr ea se d ca st ra te d m al es o r sp ay ed fe m al es D ec re as ed in ta ct m al es o r in ta ct fe m al es C as tr at ed m al es co m pa re d to a ll ot he r do gs 1 .6 8 (1 .6 -1 .7 ) S pa ye d fe m al es co m pa re d to a ll do gs O R 2 .3 5 (2 .3 -2 .4 ) In ta ct m al es co m pa re d to a ll ot he r do gs O R 0. 47 ( 0. 46 -0 .4 9) In ta ct f em al es co m pa re d to a ll ot he r do gs O R 0. 51 ( 0. 49 -0 .5 3) C ro ss -s ec tio na l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 11 93 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es o r no B re ed , s ex a nd a ge w er e an al yz ed se pa ra te ly 13 9 In cr ea se d if go na de ct om iz ed be fo re 6 m on th s O R 3 .0 ( 1. 2- 8. 0) if go na de ct om iz ed pr io r to 6 C as e- co nt ro l s tu dy R ec ru ite d fr om sp ec ia li st s in pr ac tic e 38 af fe ct ed do gs O w ne r qu es tio nn ai re /in te rv ie w 42 c on tr ol s m at ch ed f or b od y w ei gh t a nd ti bi al pl at ea u an gl e, br ee d, w ei gh t, Clinical Theriogenology • Volume 9, Number 2 • June 2017 196 m on th s of a ge bo dy c on di tio n an d ot he r va ri ab le s an al yz ed s ep ar at el y 78 In cr ea se d p< 0. 00 01 C as e- co nt ro l s tu dy P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 10 ,7 69 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s B re ed , a ge , s ex a nd w ei gh t w er e an al yz ed s ep ar at el y 73 U nc ha ng ed -- -- C as e- co nt ro l s tu dy P at ie nt s ad m it te d to a pr iv at e pr ac ti ce in E ng la nd 18 9 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es o r no C on tr ol g ro up f ro m sa m e ho sp it al , B re ed , s ex , a ge a nd ob es ity w er e st at is ti ca l a na ly si s 76 In cr ea se d D at a no t pr ov id ed C as e- co nt ro l s tu dy P at ie nt s ad m it te d to th re e sp ec ia lt y/ re fe rr al ho sp ita l 20 1 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es o r no A ge -m at ch ed co nt ro ls , b re ed , s ex an d w ei gh t w er e an al yz ed s ep ar at el y 74 In cr ea se d (f em al es ) O R 2 .1 ( 1. 6- 2. 9) C as e- co nt ro l s tu dy R eg is tr y su bm is si on s fr om p ri va te pr ac ti ce in E ng la nd 95 3 do gs R ev ie w o f re gi st ry re co rd s C on tr ol s w ith in re gi st ry p op ul at io n, br ee d, p ur eb re d or no t, se x, in su ra nc e, ag e, b od y w ei gh t w er e in cl ud ed in st at is ti ca l a na ly si s 47 In cr ea se d p< 0. 05 f or d og s go na de ct om iz ed at le ss th an 1 ye ar o f ag e R et ro sp ec ti ve co ho rt s tu dy G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 36 4 fe m al e do gs , 3 95 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n re tr ie ve rs ), s ex w as in cl ud ed in st at is ti ca l a na ly si s, bo dy c on di tio n sc or e an al yz ed Clinical Theriogenology • Volume 9, Number 2 • June 2017197 se pa ra te ly 23 In cr ea se d H R 9 .5 ( 1. 2- 74 .9 ) fe m al es ; H R 2 6. 2 (5 .6 - 12 3. 3) m al es R et ro sp ec ti ve co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 46 5 m al e do gs , 7 05 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s B re ed -s pe ci fi c st ud y (G er m an sh ep he rd d og s) , se x w as in cl ud ed in st at is ti ca l a na ly si s, bo dy c on di tio n sc or e w as a na ly ze d se pa ra te ly 49 In cr ea se d (f em al e G ol de ns ); In cr ea se d (m al e G ol de ns ); U nc ha ng ed (f em al e L ab s) ; In cr ea se d (m al e L ab s) p= 0. 03 ( fe m al e G ol de ns ), p< 0. 00 1 fo r m al e G ol de ns ca st ra te d at le ss th an 6 m on th s of a ge , p = 0. 00 4 fo r m al e G ol de ns ca st ra te d at 6 - 11 m on th s of ag e; p = 0. 02 f or m al e L ab s ca st ra te d at le ss th an 6 m on th s of a ge R et ro sp ec ti ve co ho rt s tu dy L ab ra do r an d G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 11 47 fe m al e do gs , 14 35 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n an d L ab ra do r re tr ie ve rs ), s ex w as in cl ud ed in st at is ti ca l a na ly si s, bo dy c on di tio n sc or e an al yz ed se pa ra te ly O R = o dd s ra tio , H R = h az ar d ra tio Clinical Theriogenology • Volume 9, Number 2 • June 2017 198 T ab le 1 1. L ite ra tu re r ev ie w – p at el la r lu xa ti on R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 86 In cr ea se d O R 3 .1 ( 1. 3- 7. 5) , bu t c on fo un de d by o ld er a ge as so ci at ed w it h go na de ct om y C as e- co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l, re cr ui te d th ro ug h br ee d cl ub s (s m al l a nd m in ia tu re b re ed s on ly in A us tr ia ) 43 2 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es or n o 26 2 un af fe ct ed d og s as co nt ro ls , b re ed , a ge , s ex an d w ei gh t w er e in cl ud ed in s ta tis ti ca l an al ys is 85 In cr ea se d O R 2 .4 ( 1. 8- 3. 2) , fe m al es a ls o at in cr ea se d ri sk O R 1 .3 ( 1. 1- 1. 5) C as e- co nt ro l st ud y R eg is tr y su bm is si on s fr om p ri va te pr ac ti ce s in E ng la nd 75 1 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es or n o B re ed , p ur eb re d or n ot , bo dy w ei gh t, ag e, s ex an d in su re d or n ot w er e in cl ud ed in s ta tis ti ca l an al ys is 58 U nc ha ng ed -- -- R et ro sp ec tiv e co ho rt s tu dy A ni m al s ad op te d fr om h um an e or ga ni za tio n 18 42 d og s O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in st at is ti ca l a na ly si s, lo w nu m be r of a ff ec te d an im al s m ay h av e de cr ea se d st at is ti ca l po w er O R = o dd s ra ti o Clinical Theriogenology • Volume 9, Number 2 • June 2017199 T ab le 1 2. L ite ra tu re r ev ie w – h ip d ys pl as ia R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 93 In cr ea se d G on ad ec to m iz ed do gs 1 .5 X m or e lik el y to d ev el op co nd iti on th an ar e in ta ct d og s N es te d ca se - co nt ro l s tu dy D og s re gi st er ed w ith n at io na l br ee d cl ub 97 af fe ct ed do gs O w ne r qu es tio nn ai re , ju st g on ad ec to m iz ed ye s or n o B re ed -s pe ci fi c st ud y, ag e, s ex , s li pp er y fl oo r co ve ri ng o r no t a nd ot he r va ri ab le s in cl ud ed in s ta tis tic al a na ly si s 72 In cr ea se d ca st ra te d m al es D ec re as ed in ta ct fe m al es a nd s pa ye d fe m al es C as tr at ed m al es co m pa re d to a ll ot he r do gs 1. 2 (1 .1 8- 1. 24 ) In ta ct f em al es co m pa re d to a ll ot he r do gs O R 0. 93 ( 0. 91 -0 .9 6) S pa ye d fe m al es co m pa re d to a ll do gs O R 0 .9 7 (0 .9 5- 0. 99 ) C ro ss - se ct io na l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 11 93 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es or n o B re ed , s ex a nd a ge w er e an al yz ed se pa ra te ly 58 In cr ea se d H R 1 .7 ( 1. 0- 2. 8) > 5. 5 m on th s at ne ut er R et ro sp ec ti ve co ho rt s tu dy A ni m al s ad op te d fr om h um an e or ga ni za tio n 18 42 do gs O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in sh el te r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in s ta tis ti ca l an al ys is ,, no t c le ar if a ll di ag no se s m ad e by ve te ri na ri an Clinical Theriogenology • Volume 9, Number 2 • June 2017 200 47 In cr ea se d (m al es ) p< 0. 01 R et ro sp ec ti ve co ho rt s tu dy G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 36 4 fe m al e do gs , 3 95 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n re tr ie ve rs ), s ex w as in cl ud ed in st at is ti ca l a na ly si s, bo dy c on di tio n sc or e an al yz ed s ep ar at el y 23 U nc ha ng ed -- - R et ro sp ec tiv e co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 46 5 m al e do gs , 7 05 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , br ee d- sp ec if ic s tu dy (G er m an s he ph er d do gs ), s ex w as in cl ud ed in s ta ti st ic al a na ly si s, bo dy c on di tio n sc or e an al yz ed s ep ar at el y 49 U nc ha ng ed (f em al e G ol de ns ); In cr ea se d (m al e G ol de ns ); U nc ha ng ed (f em al e L ab s) ; U nc ha ng ed ( m al e L ab s) p< 0. 00 1 fo r m al es c as tr at ed at le ss th an 6 m on th s of a ge , p< 0. 05 f or m al es c as tr at ed 6- 11 m on th s of ag e R et ro sp ec ti ve co ho rt s tu dy L ab ra do r an d G ol de n re tr ie ve rs ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 11 47 fe m al e do gs , 14 35 m al e do gs R ev ie w o f ho sp ita l re co rd s B re ed -s pe ci fi c st ud y (g ol de n an d L ab ra do r re tr ie ve rs ), s ex w as in cl ud ed in s ta tis ti ca l an al ys is , b od y co nd iti on s co re an al yz ed s ep ar at el y O R = o dd s ra tio , H R = h az ar d ra tio Clinical Theriogenology • Volume 9, Number 2 • June 2017201 T ab le 1 3. L ite ra tu re r ev ie w – u ri na ry in co nt in en ce R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 10 4 In cr ea se d R R 7 .8 ( 2. 6- 31 .5 ) P ro sp ec tiv e co ho rt s tu dy P at ie nt s ad m it te d to pr iv at e pr ac ti ce s 80 9 fe m al e do gs R ec or ds c om pl et ed b y pr iv at e pr ac tit io ne rs C on tr ol s w ith in h os pi ta l po pu la tio n, a ge , b re ed , es tr us in fl ue nc in g dr ug s w er e in cl ud ed in st at is ti ca l a na ly si s 10 8 In cr ea se d O R 4 .9 ( 3. 1- 7. 8) R et ro sp ec tiv e co ho rt P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 32 60 fe m al e do gs R ev ie w o f ho sp ita l re co rd s O nl y in cl ud ed in ta ct a nd sp ay ed a t 6 m on th s an d ol de r, n o co nf ou nd in g fa ct or s in cl ud ed 58 In cr ea se d H R 1 .2 ( 1. 1- 1. 3) ov er al l, H R 3 .5 if s pa ye d be fo re 3 m on th s of a ge R et ro sp ec ti ve co ho rt s tu dy A ni m al s ad op te d fr om hu m an e or ga ni za tio n 98 3 fe m al e do gs O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in st at is ti ca l a na ly si s 23 In cr ea se d p< 0. 05 f or d og s sp ay ed a t 6 -1 1 m on th s of a ge R et ro sp ec ti ve co ho rt s tu dy G er m an sh ep he rd d og s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l 70 5 fe m al e do gs R ev ie w o f ho sp ita l re co rd s in cl ud in g re fe rr in g ve te ri na ri an s S m al l s am pl e si ze , br ee d- sp ec if ic s tu dy (G er m an s he ph er d do gs ), a ge w as a na ly ze d se pa ra te ly 14 2 In te ra ct io n be tw ee n ag e at ne ut er a nd w ei gh t w it h lo w er r is k of in co nt in en ce f or do gs > 25 k g fo r H R 0 .8 9 (0 .8 2- 0. 97 ) R et ro sp ec ti ve co ho rt s tu dy P at ie nt s ad m it te d to A m er ic an A ni m al H os pi ta l A ss oc ia ti on ac cr ed it ed U S 35 6 fe m al e do gs R ev ie w o f ho sp ita l re co rd s C on tr ol s w ith in h os pi ta l po pu la tio n, a ge a t pr es en ta tio n an d bo dy co nd iti on s co re w er e an al yz ed s ep ar at el y; w ei gh t w as in cl ud ed in Clinical Theriogenology • Volume 9, Number 2 • June 2017 202 ev er y m on th o ld er ne ut er in g w as d on e ve te ri na ry cl in ic s st at is ti ca l a na ly si s 14 3 In cr ea se d fo r do gs > = 15 k g, a ge o f ne ut er w as n ot si gn if ic an t O R d og s > = 1 5 kg 7 ( 2. 5- 21 ) R et ro sp ec ti ve co ho rt s tu dy P at ie nt s ad m it te d to a m ul ti -p ra ct ic e ge ne ra l a nd sp ec ia lt y ve te ri na ry c li ni c 56 6 fe m al e do gs R ev ie w o f ho sp ita l re co rd s an d in te rv ie w s of o w ne rs C on tr ol s w ith in h os pi ta l po pu la tio n, b od y w ei gh t in c at eg or ie s, n um be r of li tt er s, e le ct iv e or em er ge nc y ne ut er w er e in cl ud ed in s ta tis ti ca l an al ys is 14 4 In cr ea se d w ith de cr ea si ng F S H pl as m a co nc en tr at io ns In cr ea se d w ith in cr ea si ng a ge a t sa m pl in g O R 0 .5 ( 0. 24 - 0. 91 ) FS H a ll br ee ds e xc ep t bo xe rs a nd G er m an sh ep he rd s O R 2 .7 ( 1. 3- 5. 9) ag e at s am pl in g C ro ss - se ct io na l st ud y In di vi du al p ur e br ed d og s, o ft en at d og s ho w s 49 9 fe m al e do gs In te rv ie w s w ith ow ne rs B ox er s an d G er m an S he ph er ds a na ly ze d se pa ra te ly , t im e si nc e ne ut er a nd b ef or e or af te r fi rs t e st ru s, a ge a t sa m pl in g, b od y w ei gh t, br ee d, L H a nd F S H le ve ls w er e st at is tic al ly an al yz ed . O R = o dd s ra tio , H R = h az ar d ra ti o, R R = r el at iv e ri sk Clinical Theriogenology • Volume 9, Number 2 • June 2017203 T ab le 1 4. L ite ra tu re r ev ie w – u ro li th ia si s R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 11 3 In cr ea se d, in fl ue nc ed b y ag e an d se x O R 2 .6 ( 1. 4- 4. 6) C as e- co nt ro l st ud y P at ie nt s ad m it te d to c or po ra te ve te ri na ry pr ac tic e 45 2 af fe ct ed do gs w ith st ru vi te ur ol ith s R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es or n o C on tr ol s fr om s am e ho sp ita l p op ul at io n, di et , b re ed s iz e, a ge , se x, h os pi ta l l oc at io n an d m or e in cl ud ed in st at is ti ca l a na ly si s 11 7 U nc ha ng ed O R 1 .4 ( 0. 99 - 1. 8) , p = 0. 06 C as e- co nt ro l (o xa la te v s st ru vi te ) U ro lit h ce nt er su bm is si on s 38 67 ca lc iu m ox al at e ur ol ith s, 34 30 st ru vi te ur ol ith s R ev ie w o f re co rd s ac co m pa ny in g su bm is si on s, ju st go na de ct om iz ed y es or n o N o co nt ro ls , a ge , s ex , br ee d, b od y co nd iti on , di et w er e in cl ud ed in st at is ti ca l a na ly si s 11 4 In cr ea se d, in fl ue nc ed b y ag e an d se x O R 2 .2 ( 1. 6- 3. 0) C as e- co nt ro l st ud y P at ie nt s ad m it te d to c or po ra te ve te ri na ry pr ac tic e 50 8 af fe ct ed do gs w ith ca lc iu m ox al at e ur ol ith ia si s R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om iz ed y es or n o C on tr ol s fr om s am e ho sp ita l p op ul at io n, di et , b re ed s iz e, a ge , se x, h os pi ta l l oc at io n an d m or e in cl ud ed in st at is ti ca l a na ly si s 58 U nc ha ng ed -- -- R et ro sp ec tiv e co ho rt s tu dy A ni m al s ad op te d fr om h um an e or ga ni za tio n 18 42 d og s O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in st at is ti ca l a na ly si s, , l ow nu m be r of a ff ec te d an im al s m ay h av e de cr ea se d st at is ti ca l po w er O R = o dd s ra ti o   Clinical Theriogenology • Volume 9, Number 2 • June 2017 204 T ab le 1 5. L ite ra tu re r ev ie w – d ia be te s m el li tu s R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 11 9 U nc ha ng ed (f em al es ); I nc re as ed (m al es ) O R 1 .9 ( 1. 7- 2. 2) C as e- co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry ) 68 60 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es or n o A ge - an d in st itu tio n- m at ch ed c on tr ol s, br ee d, s ex a nd w ei gh t in cl ud ed in s ta tis ti ca l an al ys is 12 1 U nc ha ng ed (f em al es ); I nc re as ed (m al es ) O R 2 .5 ( 1. 5- 4. 3) C as e- co nt ro l st ud y R eg is tr y su bm is si on s fr om p ri va te pr ac ti ce s 20 9 do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om iz ed y es or n o A ge -m at ch ed c on tr ol s, w ei gh t, br ee d an d ot he r va ri ab le s w er e in cl ud ed in s ta ti st ic al a na ly si s 58 U nc ha ng ed -- -- R et ro sp ec tiv e co ho rt s tu dy A ni m al s ad op te d fr om h um an e or ga ni za tio n 18 42 d og s O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in st at is ti ca l a na ly si s, lo w nu m be r of a ff ec te d an im al s m ay h av e de cr ea se d st at is ti ca l po w er 14 5 In cr ea se d (f em al es an d ne ut er ed m al es co m pa re d to in ta ct m al e) N o di ff er en ce be tw ee n ne ut er ed an d in ta ct f em al es R R 2 .2 ( 1. 5- 3. 0) ne ut er ed m al e re la ti ve to in ta ct m al e R R 2 .5 ( 2. 1- 2. 9) ne ut er ed f em al e co m pa re d to in ta ct m al e C as e co nt ro l st ud y P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita l ( V M D B re gi st ry a nd A ni m al M ed ic al C en te r) 14 68 d og s R ev ie w o f ho sp ita l re co rd s S ev er al d if fe re nt c on tr ol gr ou ps u se d, go na de ct om iz ed o r no t, ag e an d br ee d in cl ud ed in s ta ti st ic al a na ly si s, m on th o f di ag no si s an al yz ed s ep ar at el y. O R = o dd s ra ti o   Clinical Theriogenology • Volume 9, Number 2 • June 2017205 T ab le 1 6. L it er at ur e re vi ew – c hr on ic k id ne y di se as e R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 12 3 In cr ea se d O R 3 .2 ( 2. 1- 4. 7) , p< 0. 00 1 C as e- co nt ro l st ud y R eg is tr y su bm is si on s fr om p ri va te pr ac ti ce s in th e U K 22 8 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om y ye s or no C on tr ol s fr om r eg is tr y po pu la tio n, a ge , b re ed , se x, w ei gh t, in su ra nc e an d ot he rs w er e in cl ud ed in s ta tis ti ca l an al ys is 58 U nc ha ng ed -- -- R et ro sp ec tiv e co ho rt s tu dy A ni m al s ad op te d fr om h um an e or ga ni za tio n 18 42 d og s O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in st at is ti ca l a na ly si s , l ow nu m be r of a ff ec te d an im al s m ay h av e de cr ea se d st at is ti ca l po w er O R = o dd s ra ti o Clinical Theriogenology • Volume 9, Number 2 • June 2017 206 T ab le 1 7. L ite ra tu re r ev ie w – a to pi c de rm at it is R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 12 4 In cr ea se d R R 3 .2 ( no C I re po rt ed ) C as e- co nt ro l st ud y P at ie nt s ad m it te d to c or po ra te ve te ri na ry pr ac tic e 22 ,2 80 af fe ct ed do gs R ev ie w o f ho sp ita l re co rd s C on tr ol s fr om s am e ho sp ita l p op ul at io n, ag e, b re ed , s ex , r eg io n, ot he r di ag no se s in cl ud ed in s ta tis ti ca l an al ys is 58 U nc ha ng ed -- -- R et ro sp ec tiv e co ho rt s tu dy A ni m al s ad op te d fr om h um an e or ga ni za tio n 18 42 d og s O w ne r qu es tio nn ai re , re vi ew o f ho sp ita l re co rd s P ur eb re d or n ot , o w ne r su rr en de r or s tr ay in ta ke ty pe , t im e in s he lte r an d ot he r do gs in h ou se ho ld w er e in cl ud ed in st at is ti ca l a na ly si s , l ow nu m be r of a ff ec te d an im al s m ay h av e de cr ea se d st at is ti ca l po w er 12 5 In cr ea se d O R 2 .2 ( 2. 0- 2. 5) fe m al es ; O R 1 .5 (1 .2 -1 .8 ) m al es R et ro sp ec ti ve co ho rt s tu dy P at ie nt s ad m it te d to a s pe ci al ty / re fe rr al h os pi ta l 90 ,0 90 do gs R ev ie w o f ho sp ita l re co rd s L ar ge s am pl e si ze a nd lo w p re va le nc e of di so rd er s in s am pl e po pu la tio n m ay h av e pr om ot ed a rt if ic ia l de si gn at io n of si gn if ic an ce . R R = r el at iv e ri sk , C I = c on fi de nc e in te rv al     Clinical Theriogenology • Volume 9, Number 2 • June 2017207 T ab le 1 8. L ite ra tu re r ev ie w – e pi le ps y R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 12 6 U nc ha ng ed -- - C as e- co nt ro l st ud y R eg is tr y su bm is si on s fr om p ri va te pr ac ti ce s in th e U K 53 9 af fe ct ed do gs R ev ie w o f re gi st ry re co rd s, ju st go na de ct om y ye s or no A ge , s ex , b re ed , c ol or an d w ei gh t w er e in cl ud ed in s ta tis ti ca l an al ys is 12 8 D ec re as ed fr eq ue nc y (f em al es ), de cr ea se in c lu st er se iz ur es ( m al es ) p= 0. 00 7 in cr ea se d fr eq ue nc y of cl us te r se iz ur es in in ta ct f em al es , in ta ct m al es m or e lik el y to ha ve c lu st er se iz ur es O R 2 .3 (1 .4 -3 .9 ) cl us te r se iz ur es co m pa re d to ne ut er ed C as e se ri es C ha ri ty ve te ri na ry pr ac ti ce in U K 15 9 af fe ct ed do gs (f re qu en c y an al ys is ), 15 8 af fe ct ed do gs (s ev er it y an al ys is ) R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om y ye s or no C on tr ol s un cl ea r, ju st co m pa re d ty pe s of se iz ur es ; a ge , b re ed , s ex w er e in cl ud ed in st at is ti ca l a na ly si s 12 7 In cr ea se d O R 1 .6 ( 1. 4- 1. 9) , m al es a ls o at in cr ea se d ri sk C as e- co nt ro l st ud y P at ie nt s er a su bm it te d fo r dr ug a na ly si s 12 60 d og s R ev ie w o f do cu m en ts ac co m pa ny in g su bm is si on , D V M in te rv ie w , j us t go na de ct om y ye s or no C on tr ol s fr om la rg e pr iv at e pr ac ti ce r eg is tr y, ag e, s ex a nd b re ed w er e an al yz ed s ep ar at el y O R = o dd s ra ti o   Clinical Theriogenology • Volume 9, Number 2 • June 2017 208 T ab le 1 9. L ite ra tu re r ev ie w – li fe sp an R E F E R E N C E N U M B E R V A R IA T IO N W IT H G O N A D E C T O M Y S IG N IF IC A N T R E S U L T S S T U D Y T Y P E S U B JE C T S E L E C T IO N S A M P L E S IZ E D E T E R M IN A T IO N O F A G E A T G O N A D E C T O M Y C O N T R O L S / A N A L Y SI S F O R C O N FO U N D IN G F A C T O R S 12 9 In cr ea se d li fe sp an 23 % lo ng er (f em al es ), 1 8% lo ng er ( m al es ) C ro ss - se ct io na l s tu dy P at ie nt s ad m it te d to c or po ra te ve te ri na ry pr ac tic e 2. 2 m il lio n do gs R ev ie w o f ho sp ita l re co rd s, ju st go na de ct om y ye s or no D es cr ip ti ve s ta ti st ic s on ly 13 0 In cr ea se d li fe sp an 26 .3 % lo ng er (f em al es ), 1 3. 8% lo ng er ( m al es ) R et ro sp ec ti ve co ho rt s tu dy H os pi ta ls P at ie nt s ad m it te d to sp ec ia lt y/ re fe rr al ho sp ita ls (V M D B r eg is tr y) -- - R ev ie w o f re gi st ry re co rd s A ge in cl ud ed in st at is ti ca l a na ly si s, br ee d an d w ei gh t ev al ua te d se pa ra te ly 13 4 D ec re as ed li fe sp an -- - C as e- co nt ro l st ud y S pe ci fi c po pu la tio n of ex ce pt io na lly lo ng -l iv ed fe m al e do gs o f on e br ee d 83 lo ng - liv ed d og s Q ue st io nn ai re /in te rv i ew w ith o w ne r/ D V M 10 0 br ee d- m at ch ed co nt ro ls w ith a ve ra ge li fe sp an , b re ed -s pe ci fi c st ud y (r ot tw ei le rs ) T ab le 2 0. H il ls C ri te ri a of C au sa ti on S tr en gt h – T he la rg er th e as so ci at io n, th e m or e li ke ly th er e is a tr ue c au se -a nd -e ff ec t. C on si st en cy – S tu di es p er fo rm ed b y di ff er en t p eo pl e lo ok in g at d if fe re nt p op ul at io ns h av e co ns is te nt fi nd in gs . S pe ci fi ci ty – T he re is n o co nf ou nd in g fa ct or th at is e qu al ly o r m or e li ke ly to h av e ca us ed th e ef fe ct . T em po ra li ty – T he e ff ec t a lw ay s oc cu rs a ft er th e ca us e. * B io lo gi ca l g ra di en t – G re at er e xp os ur e le ad s to g re at er in ci de nc e of th e ef fe ct . P la us ib il ity – T he p ro po se d ca us e an d ef fe ct m ak e se ns e w it h cu rr en t k no w le dg e. C oh er en ce – A ll f in di ng s (e pi de m io lo gi c, la bo ra to ry te st in g, e tc .) s up po rt th e ca us e an d ef fe ct . E xp er im en t – T he e ff ec t c an b e al te re d th ro ug h ju di ci ou s ex pe ri m en ta l t es ti ng o f th e ca us e. A na lo gy – A ll ot he r po ss ib le c au se s ha ve b ee n ta ke n in to c on si de ra ti on . * T hi s cr it er io n m us t a lw ay s be p re se nt to d em on st ra te c au sa ti on . Clinical Theriogenology • Volume 9, Number 2 • June 2017209 T ab le 2 1. D em on st ra ti on o f po te nt ia l i n fa ul ts o f da ta a na ly si s by e va lu at io n of e ff ec t o f go na de ct om y on a v ar ie ty o f di so rd er s di ag no se d at a ve te ri na ry te ac hi ng r ef er ra l h os pi ta l D IS O R D E R p V A L U E O D D S R A T IO M A M M A R Y N E O P L A S IA 0. 7 1. 2 (0 .4 -5 .2 ) P R O S T A T IC N E O P L A S IA 0. 9 1. 1 (0 .1 -2 3. 4) T R A N S IT IO N A L C E L L C A R C IN O M A 0. 1 4. 2 (0 .6 -8 2. 9) O S T E O S A R C O M A 0. 03 4. 1 (1 .0 -2 4. 4) H E M A N G IO S A R C O M A 0. 1 2. 0 (0 .8 -5 .7 ) L Y M P H O M A < 0 .0 01 4. 0 (1 .7 -1 0. 1) C U T A N E O U S M A S T C E L L T U M O R 0. 00 2 5. 4 (1 .6 -1 9. 9) O B E S IT Y 0. 04 3. 2 (1 .0 -1 2. 8) C R A N IA L C R U C IA T E L IG A M E N T I N JU R Y < 0 .0 01 4. 8 (2 .1 -1 2. 0) P A T E L L A R L U X A T IO N 0. 06 2. 6 (0 .9 -8 .3 ) H IP D Y S P L A S IA 0. 9 1. 0 (0 .4 -3 .0 ) U R IN A R Y IN C O N T IN E N C E 0. 5 1. 3 (0 .6 -3 .2 ) D IA B E T E S M E L L IT U S 0. 3 1. 5 (0 .6 -3 .9 ) C H R O N IC K ID N E Y D IS E A S E 0. 6 1. 3 (0 .6 -3 .0 ) A T O P IC D E R M A T IT IS < 0 .0 01 3. 2 (1 .7 -5 .9 ) ID IO P A T H IC E P IL E P S Y / C L U S T E R S E IZ U R E S 0. 6 1. 3 (0 .5 -4 .4 ) U R O L IT H IA S IS – C A L C IU M O X A L A T E A N D S T R U V IT E 0. 07 2. 9 (0 .9 -1 1. 4)   Clinical Theriogenology • Volume 9, Number 2 • June 2017 210 T ab le 2 2. I m pa ct * on h ea lth o f m al e an d fe m al e do gs a ft er g on ad ec to m y (u se d w it h pe rm is si on ; R oo t K us tr it z M V . U se o f an im pa ct s co re to gu id e cl ie nt d ec is io n- m ak in g ab ou t t im in g of s pa y- ca st ra ti on o f do gs a nd c at s. C li n T he ri o 20 12 ;4 :4 81 -4 85 ) D IS O R D E R F E M A L E D O G M A L E D O G M am m ar y ne op la si a + 24 P yo m et ra + 10 0 S ur gi ca l c om pl ic at io ns -2 0 -1 6 O st eo sa rc om a -2 -2 H em an gi os ar co m a -2 -2 T ra ns it io na l c el l c ar ci no m a -7 -7 P ro st at e ne op la si a -3 T es ti cu la r ne op la si a + 5 U re th ra l s ph in ct er m ec ha ni sm in co m pe te nc e -6 6 B en ig n pr os ta ti c hy pe rt ro ph y + 36 8 R up tu re o f th e cr an ia l c ru ci at e li ga m en t -1 1 -1 1 O be si ty -1 4 -1 3 *I m pa ct s co re is d er iv ed f ro m in ci de nc e an d se ve ri ty o f di se as e. P os it iv e im pa ct s co re = b en ef it f ro m g on ad ec to m y, n eg at iv e im pa ct s co re = de tr im en t f ro m g on ad ec to m y Clinical Theriogenology • Volume 9, Number 2 • June 2017211