The Stress Response System (SRS)


The controversy with respect to spay/neuter and its negative effects upon our dogs is based upon a fundamental misconception on the part of the veterinary community. Historically, and even today, most veterinary doctors and veterinary teaching institutions take the position that sex hormones are only relevant to reproduction.

Current scientific study has established that sex hormones are responsible for much more than reproduction in dogs (and humans). Sex hormones affect canine growth and development, behavior, and a dog’s susceptibility to major diseases including cancer, diabetes and other metabolic or endocrine-related disease.

Sex hormones exert profound effects on cell growth, development, differentiation, and homeostasis. 137, 138  The concept of homeostasis is critically important to our understanding of the effects of spay/neuter upon our canine companions. Homeostasis is defined as “…the ability of the body or a cell to seek and maintain a condition of equilibrium or stability within its internal environment when dealing with external changes.” A simple example of homeostasis is the body’s ability to maintain an internal temperature around 98.6 °F for humans, or around 102 °F for dogs, despite changes in external temperature, activity and exertion.

Stress is defined as a state of threatened homeostasis (something that threatens our physical or mental stability) caused by intrinsic adverse forces (e.g., endocrine imbalance or anxiety) or extrinsic adverse forces (e.g., a physical attack).85

All living organisms must respond to change or stressors from inside and outside their body to maintain homeostasis and preserve health. The mechanism whereby canines and humans respond to stress is known as “The Stress Response System” (SRS). The SRS is charged with addressing stress in whatever form it presents, and returning the body to homeostasis. Specific areas of the Central Nervous System (CNS), which includes your brain, have critical, distinct roles, and along with the Hypothalmic-Pituitary-Adrenal (HPA) axis, form the foundation of the SRS.132  The SRS is complex–please refer to the “Hormones and the Endocrine System” section for a detailed explanation of the HPA axis. The diagram below illustrates why highly potent stressors (e.g. spay/neuter), at an early life stage, can damage the developing SRS. This damage is documented to include permanent, detrimental effects upon:

  • growth
  • reproduction
  • metabolism
  • immunocompetence
  • aging of the brain and body
  • behavior
  • patterns of emotionality
  • personality development 85, 144


Early spay/neuter surgery itself is a highly potent, acute form of stress. These surgeries are highly invasive and create an immediate interruption of sex hormone production – clearly disrupting homeostasis. The interruption of sex hormones can adversely affect:

  • Brain development – leading to behavior and personality disorders
  • Bones – leading to skeletal deformity
  • Metabolism – predisposing a dog to cancer, Cushings, obesity, diabetes and immune-mediated diseases.

For dogs who have been spayed or neutered, there will be a lifelong challenge to compensate for the loss of sex hormones. If the dog’s adrenal glands, a part of the SRS, can compensate and produce the necessary sex hormones, homeostasis will be restored. However, since hormones cannot be stored, every minute of every day is an ongoing feedback process between cells and systems of the body which require sex hormones, and the adrenal glands continuously attempting to meet the need for sex hormones. Consequently, spay/neuter is also an ongoing threat to homeostasis – a highly potent long-term form of stress that NEVER, EVER goes away.

The Role of the Central Nervous System (CNS) in Stress Response

Although brain development begins before birth, it continues well into young adulthood. There is increasing evidence that parts of the brain continue to grow, die back, and change throughout the life span. Reproductive/sex hormones have effects on all of these stages of brain growth and development.134

The brain’s dense and widespread distribution of hormone receptors, its high hormone sensitivity, and its ability to synthesize steroids through the expression of steroidogenic enzymes, among other characteristics, make it particularly vulnerable to hormonal perturbations. This concept is particularly important when put into the context of development because there are critical periods during which even minute changes in hormone exposures can affect a neurobiological outcome. This issue of sensitive life periods is central to understanding endocrine disruption’s effects on brain and behavior.176 Therefore, even a short-term lack of sex hormones (brought on by spay/neuter) can have long-term negative effects upon the structure and function of the brain as a part of the CNS. Certainly a long term lack of sex hormones which some dogs experience due to spay/neuter will have detrimental effects that can be devastating.

Functionally, a lack of sex hormones results in acute and chronic changes in brain chemistry with increased norepinephrine being most consistently documented.HAHD_SRS_BrainStructurally, a lack of sex hormones causes the hippocampus, amygdala, and prefrontal cortex to undergo stress-induced remodeling which alters behavioral and physiological responses.144 The structural changes in the hippocampal region of the brain negatively affect cognitive function and mimic the structural changes observed in early Alzheimers patients.139, 140, 141, 142   Early Alzheimer’s can cause changes in the mood and personalities of people. Patients can become confused, suspicious, depressed, fearful and/or anxious. Also, Alzheimer’s causes patients to be easily upset in locations or situations where they are out of their comfort zone.

Further, early life stress (e.g., early spay/neuter) is a major risk factor for the development of anxiety disorders (these would include generalized anxiety disorder, separation anxiety,  panic disorder, and phobias)  as well as obsessive compulsive disorder, PTSD, depression and excessive aggression and violence in adulthood.143

The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses.144  The personality changes associated with spay/neuter heighten the dog’s perception of danger and escalate the initiation of the stress response when there may be no actual threat to homeostasis. The brain’s constant misperception of situations creates dysregulation of the HPA Axis. This generally leads to a state of chronic stress, wherein the stress response is initiated, but never turns off as it should.

Exposure to chronic stress results in an overreaction to subsequent stressors and increased release of norepinephrine in the hippocampus and other brain regions.132  The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones (i.e., glucocorticoids – specifically cortisol and norepinephrine). An excess of stress and stress hormones produces detrimental effects on this brain region throughout the life course.144  Excess norepinephrine, produced by dogs with a structurally crippled SRS, may lead to behavioral problems with a degree of severity which rivals documented canine and human Post Traumatic Stress Disorder (PTSD) patients. In 2015, an ASPCA commissioned study concluded aberrant behavior related to fear, anxiety and aggression is the leading cause of dogs being surrendered to a shelter and the greatest obstacle to their subsequent adoption.172 A 2018 study66 published in the PLoS One journal links aberrant behavior related to fear, anxiety and aggression in male dogs to castration:

“The beneficial effects of gonadectomy are underpinned by the need to reduce the number of unwanted companion animals. Thousands of dogs are euthanased in shelters and pounds annually in many developed countries. However, shelters are inundated by dogs that are most commonly surrendered because they display undesirable behaviours. So the current findings present the paradox that castration may reduce the numbers of unwanted dogs but may also increase the likelihood of problem behaviours that reduce the appeal of the castrated dogs and make them more vulnerable to being surrendered.”

The Role of the HPA Axis in Stress Response

When any dog is subjected to physical, emotional or perceived stressors (e.g., orthopedic surgery, injury, rehoming), the adrenal glands respond by devoting their energy to cortisol production. For the intact dog, this is not problematic because sex hormones are still produced in the testes or ovaries. But for the spayed/neutered dog, the adrenal glands have the added burden of also producing the sex hormones. Because hormones are not stored, but must be produced as needed, stress for the spayed/neutered dog creates competing interests between cortisol and sex hormone production in the adrenal glands. Consequently, if the stress is ongoing and significant, the production of sex hormones can be interrupted entirely. This lack of sex hormones as a result of spay/neuter generally leads, at some point in time, to HPA axis dysregulation which creates adverse effects in all body systems.131 The Endocrine Society’s latest Scientific Statement on the subject of endocrine disruption explains HPA axis dysregulation (excessive cortisol and/or deficient sex hormones) in broader terms:

“…levels of any hormone must be within a physiologically relevant range to be most effective. Excursions outside of that range to superphysiological (elevated) or subphysiological (depressed) levels for any extended period nearly always result in dysfunction or disease.” 176

Dysregulation of the HPA axis has been frequently linked to anxiety related disorders and depression, as well as to violence and abnormal aggression.143  Studies have shown that animals with HPA axis dysregulation showed increased glucocorticoid (cortisol and norepinephrine) response to stressors, and demonstrated an inability to terminate the glucocorticoid response to stress.132  The hippocampus plays an important role in shutting off the HPA stress response. Hippocampal atrophy or damage (due to a lack of sex hormones and secondarily to an excess of stress hormones) impairs this shut off function and can lead to prolonged HPA responses to psychological stressors.85,144  Research has also shown that the presence of sex hormones in proper amounts helps to “turn off” the production of cortisol within the HPA axis, thereby limiting the HPA response to stress.129,135 However, in the spayed/neutered dog, excessive cortisol production precludes the synthesis of sex hormones. Therefore, the spayed/neutered dog cannot terminate the stress response and continues to produce cortisol even after the source of the stress is gone. This is consistent with studies which concluded sex steroids/hormones are an important physiologic factor that can determine the magnitude and duration of cortisol production in response to stress.135

As described by the Endocrine Society, in addition to behavioral dysfunction, recent research confirms sustained/chronic stress-related hypercortisolism (i.e., excessive cortisol produced by the adrenal glands) accompanied by sex hormone deficit135  promotes the development of some or all of the following diseases or conditions:

  • metabolic syndrome
  • fat around midsection
  • insulin resistance leading to type 2 diabetes
  • Cushings
  • decreased bone and muscle mass
  • hypothyroidism
  • hyperestrinism in male dogs
  • reduced levels of growth hormone
  • high blood pressure
  • increased triglyceride levels
  • decreased aerobic capacity
  • impaired memory and spatial cognition
  • immune suppression
  • cardiovascular conditions 85, 135, 188

Abnormal cortisol production can result in disease which affects entire organ systems.  High levels of cortisol decrease the liver’s sensitivity to insulin (i.e., insulin resistance), which increases glucose levels in the blood. If left untreated, high blood glucose (as seen in type 2 diabetes) can lead to kidney, neurological and cardiovascular damage.

It is also well documented that cortisol suppresses the immune system on multiple levels. Therefore, HPA axis hyperactivation (with overproduction of cortisol as explained above) is also indirectly associated with increased susceptibility to infectious agents and tumors.85 188 This would explain, at least in part, the elevated incidence of the following conditions that we see in spayed/neutered dogs in relation to intact dogs.

  • lymphomas
  • mast cell tumors
  • hemangiosarcomas
  • osteosarcomas
  • brain tumors in female dogs
  • skin infections
  • urinary tract infections

Additionally, studies have reported a higher incidence of tumor metastases in relation to chronic stress. Adding to the complexity of the interactions between stress and the immune system, there are also data that indicate glucocorticoids (cortisol and corticosterone) regulate immune response and suppress inflammatory reactions thereby exerting an indirect but important role in autoimmune diseases and allergies.85

Well established interactions exist between the SRS and CNS centers essential for survival such as the thermoregulatory and appetite-satiety centers. Failure of the SRS can result in an elevated core temperature and anorexia or overeating leading to obesity.85  From our personal experience, Billy and one of his neutered buddies (a Chocolate Lab named Timber) overheated quite quickly with any level of activity, even though we live in the temperate climate of San Francisco. Dysregulation of the appetite-satiety centers is implicated when dogs seemingly have an insatiable appetite, despite their continuing weight gain, which leads to obesity. Alternatively, dogs can also be diagnosed with anorexia as a result of the dysregulation of the appetite-satiety center. Preceding Billy, our spayed husky mix, Sally, was diagnosed prior to her adoption as anorexic. Billy was certainly considered anorexic by the adoption agency when we first met him, while Timber is obsessed with food. Timber’s appetite is never-ending. Post adoption, Billy continued to be a poor eater until he received anastrozole (to resolve his hyperestrinism) and supplemental testosterone. Essentially, his appetite became normal only when we balanced his hormones.

Last, and perhaps related to the issues with appetite, SRS activity is implicated in the regulation of gastrointestinal function and exhibits a strong association with gastrointestinal illness. The hypothesized method of action is independent of the HPA axis, and is quite complex. In short, gastric motility is slowed, and colonic motility is increased. Dogs have painful digestion followed by diarrhea.85  Billy had this condition as well, and vets tried numerous treatments with no success. Our only successful treatment came from a holistic vet who prescribed a daily glutamine supplement for Billy. Glutamine, including a more complete explanation of its intended uses, dosing, benefits, risks and expected outcomes, can be found on our Immunonutrition Therapy page.

So What Do I Do Now?

HPA axis integrity and precise regulation of its function are essential characteristics of the successful adaptive response to any stressor.85  This requirement for HPA axis integrity is the concept behind our efforts to determine at what point in time the adrenal glands (the “A” in the HPA axis) are no longer able to produce sex hormones to replace those lost when the dog is spayed or neutered. We advocate intervention to support adrenal function (by normalizing hormone levels) at that time to help minimize damage, as itemized above, to all body systems.

The point in exploring the topic of behavior under stress is to lend insight to most dog guardians who accept behavioral problems as an inconvenience, but do not recognize them as a harbinger of internal metabolic problems that will progress and could prove fatal. Veterinarians we consulted treated Billy’s behavior problems and his loss of fur as superficial problems, not evidence of serious internal dysfunction which would ultimately lead to serious metabolic disease that ended Billy’s life.

Consequently, guardians often see avoidance of stress or accommodating a dog’s anxiety triggers as the answer to helping their dog, but in reality it may not be enough. Stress is often experienced by the dog when the guardian may not recognize any legitimate threat actually exists. Also, a dog may learn coping mechanisms to behave in a manner you desire, yet internally the effects of stress continue to do their damage. We utilized behavioral modification methods to help Billy with his fears as a young dog, and even had some success giving him SAMe. Eventually vets diagnosed Billy with Atypical Cushings and subsequently, diabetes. The tests that the vets ran to make these diagnoses showed us that Billy had a sex hormone imbalance. The vets never addressed Billy’s hormone imbalance, even though they should have known both of these conditions could be caused or exacerbated  by a sex hormone imbalance. We were forced to do the research and figure it out on our own. Eventually, we persuaded the vets to prescribe the medications to balance Billy’s hormones, and although it was helpful, it was far too late. Had we balanced Billy’s hormones when his behavior was the only recognizable problem he had, we believe we would have been able to avoid the metabolic disease that eventually took his life. Please see our “Testosterone Supplementation” page for specifics regarding hormone balancing in a male dog that has been neutered.

Consistent with our conclusions as stated above, restoring homeostasis to the HPA axis is the primary goal of integrative care.  The philosophy of integrative care is that if stability can be reintroduced to the HPA axis, it is believed most of these deleterious conditions will be minimized, perhaps even eliminated. The tool we have to accomplish HPA axis stabilization is hormone balancing. Tests should be run to establish the levels of all relevant hormones (see our FAQ page) and methods to increase or diminish such hormones are discussed on the Countering the Effects of Spay page, the Countering the Effects of Neuter page, and the Testosterone Supplementation page.

We would suggest that special attention be given to levels of DHEA. We mention on this site that supplementing DHEA may allow female dogs to elevate their levels of estrogens safely, but as always, the levels of DHEA and other hormones should be periodically checked. However, there is evidence regarding DHEA that we had not discovered until we investigated the relationship between stress, the HPA axis and CNS. DHEA′s most overlooked but vital role may be its relationship with cortisol. DHEA has an inverse relationship to cortisol, i.e. when DHEA is low cortisol levels are elevated and vice-versa. DHEA, a glucocorticoid antagonist, serves not only to prevent excessive systemic inflammation, but also to protect the neurologic machinery, particularly the hippocampus, from the damaging effects of cortisol. Suboptimal levels of DHEA have been demonstrated in patients with numerous chronic disease states, including chronic inflammatory diseases, mood disorders and chronic pain syndromes. Exposure to chronic stress leads to a substantial reduction in circulating levels of DHEA, perhaps because the available DHEA has been utilized to reverse the classic stress-induced physiological responses as demonstrated in animal models. Hence, DHEA supplementation in certain circumstances could prove highly beneficial.

There is another property of DHEA which may explain its benefit as a supplement in certain cases. In one study, DHEA has been shown to have a neuroprotective effect against Alzheimer’s disease in ovariectomized (had their hormone producing ovaries removed) rats.171  Essentially, the investigators induced chemical changes in the brains of rats consistent with the changes seen in Alzheimer’s patients. Administration of DHEA reversed the negative changes. As we discussed earlier in this section, structural changes in the developing canine brain due to a lack of sex hormones mimic the structural changes seen in early Alzheimer’s patients (i.e., confusion, mood disorders, aggression, depression). Many spayed or neutered dogs exhibit the behavioral characteristics of early Alzheimer’s patients. For dogs affected in this manner, DHEA supplementation may be highly beneficial.

DHEA is inexpensive and can be purchased over the counter at local pharmacies or online where vitamins are sold. The micronized formulation is absorbed more completely. There are no exact dosing recommendations we can find, however, studies do tend to give a range of dosing that appears to be safe – 5 to 25 mg. orally, each morning.

As for the changes in the brain (and CNS generally), we are aware chronic stimulation of the “stress response system” does increase levels of norepinephrine in the brain. There is evidence that SAMe is able to decrease the concentration of norepinephrine in the brain.130  We discovered with Billy that SAMe was very effective in reducing his anxiety, and norepinephrine reduction may very well explain its efficacy. Practically, there are no known contraindications to SAMe in appropriate doses, and it has been used safely for a long time in humans for mood regulation, and in dogs combined with milk thistle to enhance liver function and joint comfort. Some dogs with anxiety and behavioral problems benefit from the use of antidepressants, however there is no specific protocol regarding which antidepressant works best. Also, there is the issue of unwanted side effects that all antidepressants can cause. A clear understanding of the process by which the spayed/neutered dog develops these behavioral problems would dictate that hormone balancing would be the first treatment undertaken. SAMe would be the next treatment modality as there are no documented adverse effects and it has been shown to be helpful for behavioral as well as physical problems. Antidepressants would be a last choice because they have been shown to have limited value and significant side effects.

We at Healthy and Happy Dog believe the trauma of spay or neuter surgery, as well as the resulting disruption of sex hormones, permanently damages the dog’s developing SRS. This provides an explanation for many of the disease entities and behavioral problems spayed and neutered dogs will develop throughout their life. Understanding the manner of disruption allows us to propose actions we can take to help our dogs to be as healthy as possible. Years of research brought us to the conclusion that hormone balancing, glutamine supplementation and daily SAMe tablets provided our dog Billy the greatest benefit. We hope that Billy’s life and the lessons learned from it will allow you to best provide your dog a healthy and happy life.