HPA Axis Support in Dogs and Cats

Dogs and cats experience different stressors than humans, but they can still take a toll on the body’s stress response. Supporting the HPA axis as well as addressing underlying inflammation and oxidative stress through nutritional interventions can greatly improve the quality of life in animals.

The HPA Axis

The HPA (hypothalamic-pituitary-adrenal) axis consists of the hypothalamus, pituitary gland, and adrenal glands. In both humans and animals, the HPA axis is responsible for the response to stress.₁ In dogs and cats, stress may include moving to a new home, being left alone for too long, or loud noises such as fireworks.

The adrenal glands are particularly important because they produce several hormones involved in the stress response. Cortisol is a glucocorticoid that is responsible for communicating to various systems of the body and directing their response when stress is present. It is secreted in response to stress and in proportion to the magnitude of the stressful stimuli.₁ The adrenal glands also produce and secrete:₂

• Mineralocorticoids, which control the body’s electrolyte levels
• Other glucocorticoids involved in inflammation and immune response
• Epinephrine and norepinephrine, which are catecholamines that help regulate blood pressure, digestion, and blood glucose: processes that are altered when stress occurs

The HPA axis exerts many effects throughout the body, including modulating the immune system, maintaining homeostasis, and influencing adaptation to illness._1,3 It is also closely connected to the hypothalamic-pituitary-thyroid (HPT) axis.₄ This axis consists of the hypothalamus, pituitary, and thyroid glands, with important roles in producing thyroid hormone, regulating metabolism and energy expenditure, and responding to stress. Because both acute and repeated stress can change thyroid hormone secretions, addressing underlying stress as well as issues within the HPT and HPA axes can greatly impact the health of dogs and cats.

Common HPA Axis Disorders

Hyperadrenocorticism, also called Cushing’s disease, is characterized by chronically elevated levels of cortisol, the primary stress responder in the body. Several conditions can cause elevated cortisol, but the most common cause of Cushing’s disease is the presence of a tumor in the pituitary gland. The tumor produces a hormone that triggers excessive development of the adrenal gland, resulting in excess cortisol.₅ Cushing’s disease is more common in adult and elderly cats and dogs._5,6

At the other end of the spectrum is hypoadrenocorticism, also called Addison’s disease, which occurs when there are insufficient adrenal gland hormones, including cortisol and aldosterone. Although the underlying mechanisms are not fully known, autoimmune issues likely contribute, destroying adrenal gland tissue which results in altered secretion of adrenal hormones including aldosterone.₅ Decreased aldosterone affects the levels of electrolytes in the blood, including sodium, potassium, and chloride which can cause the heart to slow down or beat irregularly. In extreme cases this can result in shock.₅ Addison’s disease is most common in young, female adult dogs.₅

Other conditions that affect the HPA axis include adrenal tumors as well as issues with the thyroid gland due to the overlap between the HPA and HPT axes. In dogs, hypothyroidism is a common issue, with clinical signs appearing when more than 75 percent of the thyroid gland has already been destroyed._7,8 Cats on the other hand are more likely to develop hyperthyroidism with excess production of thyroid hormone._9,10

Diagnostic Challenges

Accurately identifying the cause for adrenal or endocrine issues can be challenging because clinical signs are often non-specific and measures of serum cortisol do not always correlate with disease status._1,11 Adrenal gland insufficiency can also be due to issues within the pituitary gland, making it difficult to identify the root cause.₁ The current gold standard is to assess the body’s response to stress via ACTH stimulation test, the hormone that triggers release of cortisol; however, that can be costly and more difficult than checking a biomarker.₁₁

Dietary Support for HPA Axis Health

Vitamins and minerals

Vitamin A, which can be found in foods like carrots and pumpkin, is involved in regulating HPA axis activity.₁₂ Vitamin A deficiency can result in increased HPA axis activation but also decrease the expression of receptors in the brain for corticosteroids, including cortisol, which could impair HPA axis functioning.₁₂ Vitamin C is also important for HPA axis activity. It is found at high levels in the adrenal glands and is involved in the synthesis of adrenal hormones.₁₃ Maintaining adequate vitamin C status, from foods such as black currant juice and citrus fruits, can support adrenal health and the response to stress.

Manganese, an essential mineral, plays an important role in supporting the adrenal glands. It is a component of the enzyme manganese superoxide dismutase (MnSOD), which is mobilized from the liver via ACTH during the stress response.₁₅ MnSOD may be involved in reducing the formation of reactive oxygen species (ROS) that are formed during the production of steroid hormones in the adrenal glands.₁₄ Despite fluctuating dietary intake, manganese levels remain stable in the adrenal glands and are important for HPA axis function.₁₄

Anti-inflammatory compounds

Alleviating underlying inflammation can benefit animals with endocrine and thyroid issues. Supplementation with New Zealand green-lipped mussel (Perna canaliculus)can relieve inflammatory-related conditions due to the presence of many inflammation-mediating compounds, including omega-3 fatty acids, pro-resolving mediators, and antioxidants such as carotenoids and anthocyanins.₁₆ Supplementation with an anti-inflammatory nutritional supplement consisting of New Zealand green-lipped mussel, curcumin, and blackcurrant leaf extract resulted in mild clinical improvements in dogs with underlying inflammation.­₁₇

Antioxidant support

Dietary antioxidants can help reduce the consequences of excess thyroid hormone, especially in cats with hyperthyroidism. Hyperthyroidism leads to reduction–oxidation imbalance, resulting in elevated free radicals that overwhelm antioxidant defenses.₁₀ In studies investigating oxidative stress and antioxidant use in cats with hyperthyroidism compared to healthy cats, the hyperthyroid cats had significantly worse antioxidant status and significantly higher oxidative stress index.₁₀ However, treatment with antioxidants rescued organs from oxidative-stress-induced damage.₁₀ Antioxidants that support adrenal health include curcumin, quercetin, resveratrol, and vitamin E.₁₀

Whole food nutrients

Nutritional support for the HPA and HPT axes can be achieved through whole food sources rich in nutrients and bioactive compounds. Obtaining nutrients in their natural form, as part of the whole food matrix, may allow for more effective absorption and utilization.₁₈ For example, iodine is required for the synthesis of thyroid hormone but during times of high stress or when Cushing’s disease is present, excess cortisol inhibits iodine uptake by the thyroid gland. Whole food kelp provides essential iodine to help overcome this inhibition and support the HPT axis.₁₉ Additionally, reishi mushroom provides essential nutrients and may also be able to influence cortisol levels._20,21 In addition to whole food sources of important nutrients, adaptogenic herbs such as Siberian ginseng (Eleutherococcus senticosus) can also help regulate the HPA axis and stress response.₂₂

While the HPA and HPT axes are complex physiological systems in dogs and cats, nutritional support through micronutrients, anti-inflammatory compounds, antioxidants, and adaptogenic herbs can greatly enhance both adrenal and thyroid health.

References

1. Martin, L.G., Groman, R.P., Fletcher, D.J., Behrend, E.N., Kemppainen, R.J., Moser, V.R., Hickey, K.C. (2008). Pituitary-adrenal function in dogs with acute critical illness. J Am Vet Med Assoc, 233:87.
2. Dutt M, Wehrle CJ, Jialal I. Physiology, Adrenal Gland. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537260/.
3. Lensen, R.C.M.M., Moons, C.P.H., Diederich, C. (2019). Physiological stress reactivity and recovery related to behavioral traits in dogs (Canis familiaris). PLoS One, 14(9):e0222581.
4. Helmreich, D.L., Parfitt, D.B., L, X.-Y., Akil, H., Watson, S.J. (2005). Relation between the hypothalamic-pituitary-thyroid (HPT) and the hypothalamic-pituitary-adrenal (HPA) axis during repeated stress. Neuroendocrinology, 81(3):183.
5. Bruyette, D. (2022). Overview of the Adrenal Glands. Merck Veterinary Manual, Available at https://www.merckvetmanual.com/endocrine-system/the-adrenal-glands/overview-of-the-adrenal-glands.
6. Tilley, L.P., Smith, F.W.K. (2016). Blackwell’s Five-Minute Veterinary Consult: Canine and Feline.
7. Le Traon, G., Brennan, S.F., Burgaud, S., Daminet, S., Gommeren, K., Horspool, L.J.I., Rosenberg, D., Mooney, C.T. (2009). Clinical Evaluation of a Novel Liquid Formulation of L-Thyroxine for Once Daily Treatment of Dogs with Hypothyroidism. J Vet Intern Med, 23(1):43-49.
8. Mooney, C.T. (2011). Canine hypothyroidism: A review of aetiology and diagnosis. N Z Vet J, 59(3):105-114.
9. Vaske, H.H., Schermerhorn, T., Armbrust, L., Grauer, G.F. (2014). Diagnosis and management of feline hyperthyroidism: current perspectives. Vet Med (Auckl), 5:85-96.
10. Candellone, A., Saettone, V., Badino, P., Girolami, F., Radice, E., Bergero, D., Odore, R., Meineri, G. (2021). Management of Feline Hyperthyroidism and the Need to Prevent Oxidative Stress: What Can We Learn from Human Research? Antioxidants, 10(9):1496-1516.
11. Lennon, E.M., Boyle, T.E., Hutchins, R.G., Friedenthal, A., Correa, M.T., Bissett, S.A., Moses, L.S., Papich, M.G., Birkenheuer, A.J. (2007). Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc, 231:413.
12. Marissal-Arvy, N., Hamiani, R., Richard, E., Moisan, M.P., Pallet, V. (2013). Vitamin A regulates hypothalamic-pituitary-adrenal axis status in LOU/C rats. J Endocrinol, 219:
13. Patak, P., Willenberg, H., Bornstein, S. (2004). Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla. Endocr Res, 30:
14. Raza, F., Okamoto, M., Takemori, H., Vinson, G. (2005). Manganese superoxide dismutase activity in the rat adrenal. J Endocrinol, 184:77.
15. Hughes, E., Miller, S., Cotzias, G. (1966). Tissue concentrations of manganese and adrenal function. Am J Physiol, 211:207.
16. Eason, C.T., Adams, S.L., Puddick, J., Romanazii, D., Miller, M.R., King, N., Johns, S., Forbes-Blom, E., Hessian, P.A., Stamp, L.K., Packer, M.A. (2018). Greenshell ™ Mussels: A Review of Veterinary Trials and Future Research Directions. Vet Sci, 5(2):36-44.
17. Corbee, R.J. (2022). The efficacy of a nutritional supplement containing green-lipped mussel, curcumin and blackcurrant leaf extract in dogs and cats with osteoarthritis. Vet Med Sci, 8(3):1025-1035.
18. Forde, C.G., Bolhuis, D. (2022). Interrelations Between Food Form, Texture, and Matrix Influence Energy Intake and Metabolic Response. Curr Nutr Rep, 11(2):124.
19. Berson, S.A., Yalow, R.S. (1952). The effect of cortisone on the iodine accumulating function of the thyroid gland in euthyroid subjects. J Clin Endocrinol Metab, 12:407.
20. Rossi, P., Buonocore, D., Altobelli, E., Brandalise, F., Cesaroni, V., Iozzi, D., Savino, E., Marzatico, F. (2014). Improving Training Condition Assessment in Endurance Cyclists: Effects of Ganoderma lucidum and Ophiocordyceps sinensis Dietary Supplementation. Evid Based Complement Alternat Med, 2014:
21. Boonyahotra, S.S.W. (2013). Preliminary study of the applications of Ganoderma lucidum in chronic fatigue syndrome. Journal of Asian Association of Schools of Pharmacy, 2:262.
22. Panossian, A., Wikman, G., Wagner, H. (1999). Plant adaptogens III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine, 6:287.