Relationship Between Neuter Status and Cancer Highlighted by Global Differences in Neutering Practices
In the United States, it is common to neuter dogs and cats for the purpose of controlling overpopulation of stray animals, and to remove the influence of sex hormones on the development of related behaviors that may diminish the ability to enjoy the pet as a companion. Undesirable traits include marking behavior (urine), tendency to stray, and aggression. Studies have shown that a high percentage of pet owners that adopt puppies and kittens from the animal shelter do not return for neutering until after a heat cycle has occurred or a litter has been born. This reflects irresponsible pet ownership and has even been the case when there is financial incentive to return. These data have led to the habit of prepubertal neutering at ages as young as 6–8 weeks. Many animal shelters will not allow an adopted puppy or kitten to leave the facility until it has been neutered. Neutering practices have resulted in decreased euthanasia of stray animals from approximately 17 million per year to 3 million in recent years. Undesirable behaviors, however, are not entirely eliminated by neutering.
In addition to the concerns raised about removal of gonadal hormones and cancer risk, the practice of prepubertal neutering has also drawn criticism for possible negative effects on urethral development, cardiac health, and joint disease.
A well-designed epidemiologic study performed in the 1960s in a selected county in California determined that the risk of mammary cancer increased with increased exposure to sex hormones (i.e., progressive estrus cycles were associated with an increasing risk of mammary cancer to a point). This contributed to the recommendation that female dogs should be neutered prior to their first estrus. This has since been challenged, and the benefits and risks of neutering examined more closely, with regards to the risk of cancer and other conditions such as orthopedic disease. Similar findings were more recently reported in cats.
The societal practice of neutering in the United States contrasted with the lack of neutering in other countries provides an interesting opportunity to compare and contrast the occurrence and prevalence of certain diseases in dogs. In contrast to recent studies highlighting increased risk of cancer and other diseases (joint and immune-mediated disease), one large-scale study found that neutered animals were longer lived and less likely to acquire infectious, vascular, degenerative diseases or traumatic injuries.
Lifetime exposure to reproductive hormones in female dogs has been associated with the development of mammary cancer. This was also found in cats. A recent systematic review of the available literature identified 13 manuscripts that describe an association between gonadal exposure and mammary tumor development. The investigators found that most (n = 9) had a high risk of bias and of the other 4, in addition to moderate risk of bias, results were discrepant with only one finding an association. Clinical practice, however, and the abundant literature from countries outside the United States describing mammary cancer, would support an association. It is important to note, however, that mammary cancer is equally benign and malignant, and treatment with surgery is often successful.
At least two large-scale epidemiologic studies showed increased risk (odds ratio approximately 4 in both studies) of developing prostate cancer in male dogs that had been neutered. The use of dogs with spontaneously occurring prostate cancer as a model of hormone-refractory prostate cancer in men has been recognized.
Hemangiosarcoma is among the most aggressive cancers that we identify and attempt to treat in dogs and cats. Highly metastatic, the long term survival is low. Golden Retrievers are overrepresented and a recent investigation into the risk of developing this cancer showed increased risk in dogs that were neutered after 1 year of age. This was also seen in an unpublished study with data derived from a large database. The similar risk for intact females and those neutered at less than one year of age in the first cited study begs an answer as to the mechanism. The authors propose a priming effect whereby dogs that have never been exposed to sex hormones do not develop a dependence or sensitivity to them.
Several reports now exist regarding an association of neuter status with lymphoma. In a recent report in Golden Retrievers, neutered males developed lymphoma 3 times more often than intact males. This was confirmed with a subsequent analysis by the same group in which dose-response associations were attempted by breaking out groups based on age at neutering. Another, database origin, epidemiologic study supported a protective effect of female reproductive hormones with intact females at lowest risk of developing lymphoma among studied groups. In a self-reporting survey-based study, Vizslas were more likely to develop lymphoma or other cancers (mast cell tumor or hemangiosarcoma).
In an epidemiologic study of 683 Rottweiler dogs, a statistically significant association was detected between age at gonadectomy and risk of bone cancer (which developed in 12% of dogs). Osteosarcoma developed in approximately 25% of dogs neutered prior to one year of age, and this was statistically greater than intact counterparts. The relative risk for both male and females dogs was greater than 3. In addition, it appeared that the longer a dog was sexually intact, the lower the rate of osteosarcoma, though this was not statistically significant. While hypotheses about the pathogenesis of osteosarcoma include effect of rapid growth and heavy body type on the physis, the findings in this study were independent of both height and weight of the dogs. In a related study, intact female Rottweilers were more likely to live longer than the expected life span.
Mast Cell Tumor
A few reports have documented an increased risk of mast cell tumor in neutered animals. In one large case control study, neutered females were more likely to develop mast cell tumor than their intact counterparts. This was echoed by the Vizsla study and the Golden Retrievers study discussed in sections above.
Current literature supports a protective effect of sex hormones against several forms of cancer. In addition, it would seem that for those cancers that are potentially promoted by sex hormones, such as mammary cancer, treatments are often successful whereas cancers that develop in the absence of sex hormones such as hemangiosarcoma or osteosarcoma are aggressive and difficult to manage or cure. Unfortunately, though current literature has much good information, a true dose-response relationship of hormones to cancer has not been fully shown. However, the effect of hormones on predilection for cancer may be much more complex and involve alterations in the DNA that do not relate to duration of gonadal exposure but rather to timing. The comparison of cancer rates and clinical behaviors of various cancers among developed countries provides unprecedented epidemiologic data that should continue to accrue.
1. Cooley DM, Beranek BC, Schlittler DL, Glickman NW, Glickman LT, Waters DJ. Endogenous gonadal hormone exposure and bone sarcoma risk. Cancer Epidemiol Biomarkers Prev. 2002;11(11):1434–1440.
2. Teske E, Naan EC, van Dijk EM, van Garderen E, Schalken JA. Canine prostate carcinoma: epidemiological evidence of an increased risk in castrated dogs. Mol Cell Endocrinol. 2002;197(1–2):251–255.
3. Bryan JN, Keeler MR, Henry CJ, Bryan ME, Hahn AW, Caldwell CW. A population study of neutering status as a risk factor for canine prostate cancer. Prostate. 2007;67(11):1174–1181.
4. Torres de la Riva G, Hart BL, Farver TB, et al. PLoS One. 2013;8(2):e55937.
5. Hart BL, Hart LA, Thigpen AP, Willits NH. Long-term health effects of neutering dogs: comparison of Labrador Retrievers with Golden Retrievers. PLoS One. 2014;9(7):e102241.
6. Schneider R, Dorn CR, Taylor DO. Factors influencing canine mammary cancer development and postsurgical survival. J Natl Cancer Inst. 1969;43(6):1249–1261.
7. Beauvais W, Cardwell JM, Brodbelt DC. The effect of neutering on the risk of mammary tumours in dogs - a systematic review. J Small Anim Pract. 2012;53(6):314–322.
8. White CR, Hohenhaus AE, Kelsey J, Procter-Gray E. Cutaneous MCTs: associations with spay/neuter status, breed, body size, and phylogenetic cluster. J Am Anim Hosp Assoc. 2011;47(3):210–216.
9. Zink MC, Farhoody P, Elser SE, Ruffini LD, Gibbons TA, Rieger RH. Evaluation of the risk and age of onset of cancer and behavioral disorders in gonadectomized Vizslas. J Am Vet Med Assoc. 2014;244(3):309–319.