One of the most controversial topics in the veterinary cancer field is the potential effect of gonadectomy on cancer risk. Spaying and neutering have obvious benefits with regard to population control and in preventing ovarian and testicular cancers. However, over the past five years, several studies have found a correlation between early spay and neuter practices and cancer diagnosis. The previously accepted connection between mammary tumor risk and spay also has been questioned. This article examines the data available connecting cancer and gonadectomy, and explores how the results can and should impact discussions with pet owners considering the procedure. The Hoffman Study The largest study to date assessing the effects of gonadectomy studied the lifespan and cause of death of more than 70,000 dogs in the Veterinary Medical Database. In this study by Hoffman et al, sterilized dogs lived, on average, 1.5 years longer than intact dogs, and sterilization increased life expectancy by 13.8 percent in males and 26.3 percent in females. The study also found that sexually intact dogs were more likely to die of infectious disease, trauma, vascular disease and degenerative disease, and sterilized dogs were more likely to die of neoplasia and immune-mediated disease. When looking at specific cancers, intact females were more likely to die of mammary cancer, and sterilized dogs were more likely to die of transitional cell carcinoma, osteosarcoma, lymphoma, mast cell tumors or prostate cancer. The results of this study have significant implications on data published in other studies, as they connect longer life with higher cancer rates. Mammary Tumors In humans, the role of hormones in breast cancer development is well established. Estrogen, in particular, is known to stimulate growth of stromal and ductal tissues in the breast and increase mitotic activity of breast epithelium, and it can recruit noncycling epithelial cells into the cell cycle. Estrogen also regulates specific genes that, when mutated, contribute to cancer development. In women, overall lifetime estrogen exposure has been correlated to breast cancer risk, which increases with a younger age at menarche, older age at menopause, fewer children and hormone replacement therapy. Less research has been done in pets compared to humans, but data connecting ovariohysterectomy and a decreased incidence of mammary tumors has been published since 1969. The often-quoted study by Schneider et al found that 72 percent of dogs diagnosed with mammary tumors were intact at the time of diagnosis. Also, out of the spayed dogs, 75 percent were spayed before 30 months of age. This study also found the lowest risk of mammary tumor development in dogs spayed before the first heat, but only one dog was spayed before that occurrence and three dogs before the second heat, so results should be interpreted with caution. Further study into spay timing and mammary tumor risk is necessary. Timing of ovariohysterectomy also has been shown to be associated with mammary cancer risk in felines. A case-control study in cats found a decreased risk of tumor development compared to intact cats in those spayed before 2 years of age. Risk was reduced by 91 percent in cats spayed before 6 months of age, by 86 percent if spayed between 6 months and 1 year, and by 11 percent if spayed between 1 and 2 years of age. Based on this paper, it may be ideal for cats to be spayed before 1 year of age to have maximum protection against mammary tumors. In 2012, a paper published in the Journal of Small Animal Practice aimed to systematically review the quality of publications reporting a connection between spay and risk of mammary tumors. The authors concluded that the evidence that neutering reduces the risk of mammary neoplasia is weak. To reach this conclusion, the authors used the SIGN (Scottish Intercollegiate Guidelines Network) levels of evidence system in which only meta- analyses, systematic reviews and high-quality case control or cohort studies are considered high levels of evidence. In veterinary medicine, there are very few studies on any topic that qualify as described, and, using these criteria, much of what we do as veterinarians would be considered to be based on weak or unsound data. As the data came into question, Hoffman’s paper was published with a very strong correlation between intact reproductive status and death due to mammary cancer, strengthening the available evidence. Other Cancers The Hoffman study found a higher risk of death due to bladder and prostate cancer, osteosarcoma, lymphoma and mast cell tumors in sterilized dogs. These dogs also lived significantly longer than their intact counterparts and had a lower risk of death from infectious, traumatic and other conditions, which likely influenced results. With these confounding factors, it’s difficult to know whether the increased risk of cancer could be related to hormonal factors. Several breed-specific publications also have reported a higher risk of diagnosis of certain cancers after gonadectomy. A study of Vizslas found a higher risk of mast cell tumors, hemangiosarcoma and lymphoma in spayed and neutered dogs. Another study of golden retrievers also found higher risk of the same three cancers in gonadectomized dogs, and a study of Rottweilers found that risk of osteosarcoma diagnosis increased with younger age at gonadectomy. Also, several studies have been published supporting a higher incidence of prostate and bladder cancer in neutered male dogs compared to intact male dogs. While the findings in these studies might suggest a real correlation may exist between cancer risk and gonadectomy, some of these publications have weaknesses that must be addressed with additional research. The Vizsla study relied on client reporting for its data, potentially biasing the results due to owner preconceptions. The golden retriever study excluded dogs greater than 8 years of age, and, along with the Rottweiler study, did not account for bias due to potentially longer lifespans in spayed or neutered dogs. Another potential source of bias could be due to differences in owner pursuit of healthcare. Not all pet owners elect to see a veterinarian regularly, and it’s possible that owners who chose to spay or neuter their dogs were more likely to seek out veterinary care. As a result, they may have been more likely to seek diagnostic tests that lead to a specific cancer diagnosis, while those who do not seek out care may die or be euthanized without a specific diagnosis. As a result of this bias, it could appear that spayed and neutered dogs have a higher incidence of cancer, and further investigation into the true influence of this bias is necessary. Interpreting the findings of these publications and discussing them with owners in a clinical setting also should include a consideration of the real numbers. For example, in the Hoffman study, the differences in frequency of cancer deaths were between approximately 5 and 15 percent. For example, the percentage of spayed or neutered dogs between 5 and 10 years of age that died from cancer was approximately 62 percent compared to approximately 53 percent of intact dogs. While any single cancer diagnosis is devastating to an owner, the clinical implications of relatively small increases in diagnosis frequency should be considered. Nonneoplastic Considerations The effect of gonadectomy on factors other than cancer must be considered when making recommendations to owners. Research has attempted to study the correlation between reproductive status and behavior, orthopedic disease and immune-mediated disease. The data relating to reproductive status and behavioral problems in dogs are conflicting, with some studies finding a higher risk of behavioral problems in intact dogs and others finding a lower risk. Immune-mediated diseases have been correlated with gonadectomy, and two studies have found a higher risk of diagnosis in sterilized dogs of such diseases as atopy, immune-mediated hemolytic anemia, hypothyroidism and inflammatory bowel disease. Hormones also can play a role in bone and joint maturation, and a higher risk of hip dysplasia and cruciate tear have been found in dogs spayed or neutered before 1 year of age. Though further research is necessary, these factors may influence an owner’s opinions on sterilization procedures and timing. Ultimately, prospective studies are necessary to fully investigate the association between neutering and certain cancers. The golden retriever lifetime study currently underway will hopefully provide prospective data while controlling for breed and healthcare selection bias. This is the first prospective study that may be able to best assess cancer incidence based on a number of variables including gonadectomy. In the meantime, conversations with owners should include consideration of the individual pet as well as owner circumstances and risk tolerance. For owners interested in pursuing gonadectomy who are concerned about cancer risk or orthopedic effects, a recommendation to spay or neuter after 1 year of age but before 30 months of age may be a good middle ground in which mammary cancer risk is still low but risk of orthopedic disease is less. At this time, it may be premature to make recommendations for or against gonadectomy based on available data related to risk of nonmammary cancers, given the longer lifespans found in sterilized dogs. The results of future prospective research in this field may further guide us and are eagerly awaited. Dr. Katherine Skorupski is an associate professor of clinical medical oncology at the University of California, Davis, School of Veterinary Medicine.
