Given that I recently presented a couple of evidence-updates on the subject the health effects of neutering, the timing was excellent for the release last week of a new research study looking at the same issue.

Torres de la Riva G, Hart BL, Farver TB, Oberbauer AM, Messam LLM, et al. (2013) Neutering Dogs: Effects on Joint Disorders and Cancers in Golden Retrievers. PLoS ONE 8(2): e55937. doi:10.1371/journal.pone.0055937

This was a retrospective cohort study in which records were searched to identify Golden Retrievers who had been patients at the UC Davis veterinary school, were between 12 months and 8 years of age, and who could be classified as having been neutered “early” (before 12 months of age), “late” (after 12 months of age), or not at all. The occurrence of a number of diseases common in Golden Retrievers was then evaluated to see if it differed between dogs in these three categories. There are several reasons to be cautious in how we interpret the results of this study, but let’s start by looking at what those results were.

The authors looked at the occurrence of hip dysplasia (HD), elbow dysplasia (ED), cranial cruciate ligament rupture (CCL), and a number of cancers com including lymphosarcoma (LSA), hemangiosarcoma (HSA), mast cell tumor (MCT), osteosarcoma (OSA) and mammary cancer (MC). The figures below illustrate the relative occurrence of some of these diseases in males and females by neuter status (the diseases not shown did not occur often enough to be included in the analyses).

Figure 1. Percentages and number of cases over the total sample size for each neutering status group; intact and neutered early or late for male Golden Retrievers (1–8 years old) diagnosed with hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and/or mast cell tumor (MCT) at the Veterinary Medical Teaching Hospital of the University of California, Davis, from 2000–2009.

For HD and LSA, the differences between early-neutered and intact or late-neutered groups were statistically significant (K-M), as were differences for CCL between intact and early-neutered groups.

Figure 2. Percentages and number of cases over the total sample size for each neutering status group; intact and neutered early or late for female Golden Retrievers (1–8 years old) diagnosed with hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and/or mast cell tumor (MCT) at the Veterinary Medical Teaching Hospital of the University of California, Davis, from 2000–2009.

For CCL the difference between intact and early-neutered was statistically significant (K-M). For HSA, the differences between early and late-neutered and intact and late-neutered groups were statistically significant (RR), as were differences for MCT between early and late-neutered groups. A similar statistical comparison for late neutering and intact groups was not possible for MCT because there were 0 cases in the intact group.

doi:10.1371/journal.pone.0055937.g002

These results suggest that there is a complex and inconsistent pattern of associations between neuter status and these diseases. In general, there was a tendency for neutered animals to have higher rates of these diseases than intact animals and for early neutered animals to have higher rates than late neutered animals. However, there are many cases in which differences were not statistically significant or the difference was significant in one sex but not the other, and a few in which the direction of the difference was opposite that expected (for example with HAS occurring more often in late-neutered females than either intact or early neutered females).

The difficulty lies in knowing what these results mean in terms of predicting the risks for individual pets and making decisions about neutering in general. The natural tendency will be to look at these data and conclude that not neutering, or neutering after 12 months of age, is safer than the common current practice of neutering most animals before 12 months. However, this is not a conclusion we can reliably draw from these data.

To begin with, this is a group of dogs that are, in many ways, very different from most dogs neutered by veterinarians. Apart from only representing one breed, and a breed known to have higher rates of the diseases studied than most other breeds, the subjects were patients at a university veterinary hospital. In general, only the sickest animals with the most unusual or serious diseases are seen at universities. Most healthy animals or those with typical illness are seen at general veterinary practices. So it is uncertain if neutering will have the same effects as in this study on dogs of other breeds or those healthy enough to have never seen the inside of a university hospital.

The population also contained small numbers of intact and “late” neutered dogs. This makes it more likely that small, random differences in the health of individual dogs in the study group could alter the apparent effects of neutering on health.  And the authors chose to limit the study population to dogs between 12 months and 8 years of age. Quite a few Golden Retrievers live past 8 years, and the rates of cancer generally go up dramatically with age. If the proportion of these diseases among intact and neutered animals over 8 years old are at all different from those in dogs under 8, then the direction and statistical significance of the differences between groups seen in this study could easily be altered.

And it’s important to consider the absolute risk and benefit numbers when making decisions about whether to neuter. If, in fact, neutering is strongly protective against a common cancer (as it is thought to be for mammary cancer) but also slightly increases the risk of a rare cancer, it may still make sense to neuter early depending on the unique situation of an individual patient.

Finally, two of the major diseases against which neutering is thought to be protective in females, uterine infection and mammary cancer, did not occur often enough to be included in the analysis. This may be because relatively few of the dogs were intact or because of the age cutoff. Obviously, if there really is a protective effect of neutering on these diseases that didn’t show up in this study, that might influence the interpretation of the results.

Overall, this is a useful piece of research adding to the information we have about the pros and cons of neutering and the possible role of age in the effect of neutering on disease. It should be over-interpreted as the final word by itself, but it should be incorporated into a broad analysis of all the available evidence.

As it stands, there is reason to believe early neutering has significant benefits in females, though as the recent systematic reviews pointed out the evidence behind this belief is not strong. There is also reason to be concerned about possible risks, though the evidence for this is also not robust yet. On balance, one can make a reasonable case on both sides, and the risk profile for individual dogs, as well as larger issues such as the problems associated with unwanted reproduction. Anyone who says there is an absolute and universal right answer concerning if and when to neuter female dogs is exaggerating by quite a bit.

For males, I believe the evidence of benefits from neutering, especially before 12 months of age, is not compelling, and I don’t see a strong reason to neuter earlier in the case of owned dogs with owners willing to commit to preventing roaming and unwanted reproduction and in the absence of intolerable interdog aggression. For large breeds in particular, delaying neutering of males seems reasonable, though we very much need better evidence to have confidence in such a recommendation. It is encouraging that more attention is now being paid to the complexities of neutering and the risks and benefits associated with it, and I am optimistic that this will lead us to more reliable guidelines in the future.

This is another in my series of evidence updates on the risks and benefits of neutering in dogs and cats. I will be updating the evidence and conclusions of my original 2010 review based on a series of systematic reviews being produced by a research group in the UK. The first such update concerned the effect of neutering and age at neutering on urinary incontinence in female dogs. This update concerns one of the most important reasons to considering neutering female dogs: mammary cancer.

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 Jun;53(6):314-22.

In my 2010 review, I found evidence suggesting that mammary cancer is very common in intact female dogs, that it is malignant about half the time, and that neutering dramatically reduces the risk of this disease. I also found evidence suggesting that neutering is most effective in preventing mammary cancer if performed before the first heat, and that the benefit disappears after the third estrus cycle. This is a major reason why I still recommend neutering young female dogs.

The UK group found only 4 research reports that addressed the question of the impact of neutering on mammary cancer risk and that met the minimum quality criteria for review. One of these also addressed the issue of whether age at neutering was associated with mammary cancer risk. They reported the following results: 

1. All studies had significant methodological flaws, and none provided information that could be confidently generalized to the general dog population.
2. One study found a strong protective effect of neutering. Another found some protective effects but these were inconsistent. The remaining two studies found no association between neutering and mammary cancer risk.
3. The one study that evaluate age at neutering found a significant decrease in the protective benefits of neutering with each of the first three heats, and no benefit after the third heat.

Once again, the general conclusions are consistent with the current consensus, that neutering young female dogs likely has a meaningful beneficial effect on reducing the risk of mammary cancer later in life. However, the existing evidence is extremely weak, and this conclusion has to be viewed as tentative. While current evidence does not justify a change in the common practice of recommending neutering to prevent mammary cancer, we cannot view our current conclusion with any great confidence, and we desperately need more and better quality research to determine if the current evidence is correct or if a significant change in our recommendations is called for.

As always, the decision to neuter must be based on the entirety of the known risks and benefits, with a clear understanding of the uncertainty involved, as well as on the unique circumstances of each individual. The value of this review is not so much in answering our questions about the subject, which it cannot do, but in making it clear what the strengths and weaknesses are in the evidence behind our current recommendations and in guiding us in the development of better evidence that will permit more confident conclusions.

A couple of years ago, I wrote a review of the risks and benefits of neutering. This handout, originally intended for clients, was also turned into a journal article for veterinarians:

Evaluating the benefits and risks of neutering dogs and cats CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources 2010 5, No. 045

This was a narrative review, not a systematic review. This means that I found as many research reports as possible related to the subject and informally evaluated their conclusions. I did not conduct a formal appraisal of the level and quality of the research evidence according to predetermined and standardized criteria, as would be done in a systematic review.

There are pros and cons to each format. A narrative review is more likely to reach pragmatic conclusions based on the existing evidence, whereas a systematic review is more likely to end with no useful conclusion if the quality of the evidence examined is less that perfect, which it almost always is. However, a systematic review is likely to be more thorough and provides a better picture of how strong the existing evidence is so that it is possible to gauge how much confidence we ought to have in the conclusions we base on it.

As a practicing clinician, I need to make practical decisions even when the evidence isn’t perfect, so a narrative review was more suited to my goals. However, as a strong supporter of the practice of evidence-based veterinary medicine, I believe systematic reviews and a clear understanding of the limitations of the available evidence on specific subjects is critical to making fully informed decisions. So I am thrilled to see that a research group in the U.K. has begun producing a series of systematic reviews of the evidence concerning the risks and benefits of neutering in dogs. I intend to evaluate these reviews as they appear to help update and appraise the evidence on this important subject and provide a bit of context for veterinarians and pet owners trying to make practical decisions about neutering. The first subject reviewed was the potential effect of neutering on the risk of urinary incontinence.

Beauvais W, Cardwell JM, Brodbelt DC.The effect of neutering on the risk of urinary incontinence in bitches – a systematic review.J Small Anim Pract. 2012 Apr;53(4):198-204.

In my 2010 narrative review, I was only able to report research suggesting urinary incontinence was common in spayed female dogs and that the research was conflicting on whether incontinence was more common in dogs spayed at younger ages. I did not identify specific research comparing the occurrence of incontinence in intact and spayed females.

The UK group identified only one research study evaluating the relative risk of incontinence in neutered and intact dogs, and three studies evaluating the effect of age at neutering on incontinence risk. The authors concluded the following:

1. All the evidence was weak, with a significant risk of error

2. The one study that evaluated risk of incontinence with neutering found that neutering significantly increased the risk of incontinence.

3. Two of the three studies found no association between age at neutering and incontinence and one found that incontinence was more likely the younger dogs were when neutered.

So the conclusions are consistent with the current consensus, that neutering female dogs does increase the risk of urinary incontinence and that age at neutering probably does not affect this risk significantly. There is, of course, significant uncertainty because the evidence is quite weak. That does not mean, however, we cannot reach a conclusion or make recommendations. If this were the case, we would almost never be able to decide anything in medicine since the evidence is often imperfect. It simply means that we have to acknowledge the uncertainty and recognize that our conclusions are provisional and might need to change as new evidence emerges.

Any decision about neutering should not, of course, be based solely on this single issue. Urinary incontinence, while inconvenient, is a relatively minor and highly treatable clinical problem. And there are a large number of other risks, benefits, and personal considerations involved in making a decision about neutering. The important thing is that we make informed decisions and that we understand the strengths and weaknesses in the available evidence. The reviews produced by this group will be invaluable in facilitating this.

I have written about a wide variety of conventional and alternative therapies for arthritis pain in dogs. A recurring issue in evaluating these therapies is how we know whether or not interventions designed to reduce pain in animals are effective. While I do not think dogs have beliefs or expectations about their treatment, and so do not experience the kind of direct placebo effect people can, they can manifest differences in both the objective features of their illness and in the symptoms they exhibit when given placebo therapies, due to a variety of effects others have described (e.g. classical conditioning, human interaction, etc.).  The indirect placebo effect of a therapy on the vets and owners involved in studying a pain control treatment for dogs are well-documented, and these frequently lead us to believe such therapies are effective when they aren’t. So finding a reliable, repeatable, and accurate measure of the effect of a pain medication is critical.

The gold standard for testing arthritis medications in dogs is force plate analysis. This tool involves having a dog walk across a plate that records the amount of weight carried on each limb. As pain is decreased with treatment, lameness improves and the amount of weight the dog can carry on the affected limb increases. This is a technically challenging tool, but the most accurate and objective way we have of knowing if we have successfully diminished pain in a dog’s limb.

A subjective measure of some kind is often used in arthritis treatment studies instead of force plate analysis because such tools are easier and less expensive to use. With proper blinding and controls, subjective evaluations by owners and veterinarians can have some value in measuring response to pain treatment. However, the results of such evaluations are often inconsistent, and the risk of uncontrolled placebo effects is high.

A new study has attempted to validate a subjective owner rating tool by comparing the results of this survey to force plate analysis in dogs with newly diagnosed arthritis given a NSAID or a placebo.

Brown DC, Boston RC, Farrar JT.Comparison of force plate gait analysis and owner assessment of pain using the canine brief pain inventory in dogs with osteoarthritis. J Vet Intern Med. 2013 Jan;27(1):22-30.

The dogs in this study were assessed by force plate gait analysis the first day, and the owners completed a previous validated questionnaire about pain and the degree to which it interfered with their pets’ activities. The dogs were then randomly assigned to either a placebo or NSAID treatment and re-assessed in 2 weeks.

As expected, the dogs on NSAID therapy showed a significantly greater increase in the weight placed on their arthritic limbs than those placed on the placebo. This objectively showed that the medication improved their lameness, and presumably their pain. The two measures of effect in the client questionnaire also showed significant improvement in dogs on NSAID compared to dogs taking placebo. This would seem to show that the questionnaire also accurately identified the improvement in pain on the medication..

However, the authors also found that there was no correlation or concordance between the survey measures and the force plate analysis. In other words, while overall the survey scores changed in the expected way, the survey scores and force plate analysis measurements for individual dogs didn’t seem to be related or to change together.

What does this mean? Well, the authors argue that both the survey and force plate analysis are measuring real improvements in pain, but the force plate specifically measures the change in lameness associated with treating pain while owners are measuring more general signs of comfort and normal activity at home. This is certainly a plausible explanation, but it doesn’t entirely make sense.

If the drug reduces pain, and pain is causing the lameness, then as pain decreases the lameness should decrease. The force plate results show that this is what is happening. However, if the surveys are also measuring accurately the reduction in pain, even if they are not measuring lameness, then the decrease in pain and the improvement in lameness should occur together and the two measures should correlate.

Think of it this way. Let’s say we want to measure the effect of a drug in reducing nausea and vomiting. If we count the number of episodes of vomiting, and the drug clearly reduces how often a person throws up, then that is an objective, though indirect, measure of nausea (analogous to force late analysis evaluating pain by measuring lameness). And if we ask people about their nausea, and if they say they are less nauseated when taking the drug, that is another way to measure nausea and the effect of the drug (analogous to asking clients about their dogs’ pain). But if both tests are measuring the same thing, then the results should correlate. People who say they feel less nauseated should vomit less than people who say they don’t feel any better.

But what happens if we give the drug and on average the group reports they feel less nauseated and overall they vomit less, but the individual responses on the survey don’t match the frequency of vomiting? People who say the feel better might or might not vomit less. And people might show less vomiting even when they say they don’t feel any less nauseated. Are the survey and the frequency of vomiting both measuring nausea? And which is more important? Do we primarily want people to report feeling better but still vomit just as much, in which case the survey might an appropriate tool? Or is it more important to reduce the amount of vomiting even if some people who vomit less say they don’t feel better?

In the case of arthritis pain in dogs, it is difficult to picture a situation in which reducing the signs of pain perceptible by the owner is more important than reducing the lameness caused by the pain. This raises the question not only of what the owner survey is actually measuring but also the question of when would it be an appropriate tool to use to measure the efficacy of an analgesic therapy. If animal owners report their pets have less pain but we don’t have an objective measure such as force plate analysis, it seems likely that the intervention is changing something about the dogs’ behavior which the owners are detecting, but it isn’t clear that something is pain.