The HPA Axis

The HPA axis links our body to the outside world and helps us to respond to the environment which surrounds us. The concept of management of the HPA axis through nutrition and lifestyle in order to influence wellness and disease management has been advocated for quite some time in functional medicine. The importance of the HPA axis to overall health and wellbeing is now being evaluated in the laboratory and with clinical research, and interesting information is emerging.  

The term HPA axis refers to a set of complex interactions and dialogue between the hypothalamus, pituitary and adrenal glands. Aspects of this axis can also impact on other endocrine functions such as the thyroid and ovaries, leading to global alteration of the body's response to stressors, immunity, inflammation, metabolism, hormone balance, energy, emotions, mood, sexuality and other important processes.

While the conversation and its regulation of the HPA axis can be quite complex, the axis can be simplified as follows:


Located in the brain.

Contains neurons which secrete vasposressin and corticotropin- releasing hormone (CRH).

Vasopressin and corticoptropin releasing hormone regulate the anterior pituitary gland.


Located in the brain.

Secretes adrenocorticotropin hormone (ACTH) in response to CRH.

ACTH acts on the adrenal gland.

Adrenal Gland

Small glands located on the top of each kidney.

Responds to ACTH to produce cortisol.


The stress hormone.

Impacts on many processes of the body

The healthy release of cortisol occurs in a circadian rhythm in humans. Cortisol levels in a well individuals peaks in the morning just after arising, the levels then fall throughout the day, peak again in the late afternoon and then fall in the late evening, where they reach a trough in the sleeping hours. The release of CRH from the hypothalamus can be altered and influenced by stress, illness, and physical activity.

The HPA axis plays an important role in many metabolic functions in the body and impacts on many organ systems such as the cardiovascular system, energy extraction, immune system, hormone balance and the central nervous system. The HPA axis links physical health and emotional (psychosocial) health together to affect how the body functions. When the natural circadian rhythms of cortisol are affected by stress, emotions, or physical illness, this disruption can lead to problems with: sleep, chronic fatigue, pain and additional illness or inability to heal.

Stressors, including emotional stressors are processed in the brain through the amygdala, hippocampus, prefrontal cortex, and hypothalamus to affect the HPA axis. As stress increases cortisol levels, multiple body processes are affected. Available glucose is increased for a body in stress, while other processes such as the immune system, begin to be shut down in order to redirect energy. The chronic over production of cortisol can lead to aberrant function of multiple organ systems. For example, the immune system may be inappropriately become over active.

Differing forms of stressors may lead to varied alterations of the diurnal cortisol release patterns. For example, with chronic stress, such as PTSD there is a blunted cortisol response. Prenatal and early life stress can also affect the HPA axis. Laboratory experiments have demonstrated that prenatal stress can lead to an exaggerated HPA axis response to later stressors. Laboratory animals exposed to prenatal stressors have altered circadian release of cortisol throughout their lives. The data is now emerging that in humans prenatal stressors can lead to changes in the HPA axis and resulting in altered brain functioning in children. Early life stressors have been well evaluated in animal studies, demonstrating that extreme stress can lead to prolonged alteration of the HPA axis into and through adulthood.

The contribution that the HPA axis makes to metabolic processes of the body is beginning to be elucidated:

Immune System

There is a bidirectional crosstalk between the HPA axis and the immune system. The HPA axis contributes to modulating inflammation in the body. In addition, the immune system can contribute to the function of the HPA axis, as pro inflammatory compounds, called cytokines, can activate the HPA axis and alter neurotransmitters so that depression and fatigue, as well as other mood changes can occur. It is now thought that inappropriate function of the HPA axis can lead to inflammatory conditions such as allergies and auto-immune reactions.


The HPA axis is also active in the origins of mood disorders, sleep disorders, anxiety, depression, ADHD, fatigue and “burnout”, IBS and other illnesses. Stressors, both physical and emotional, can affect the function of the HPA axis. Serotonin, dopamine, and norepinephrine contribute to regulation of the HPA axis. This is how some medicinal antidepressants exert their effects. Serotonin (5HT) is involved in mediating the stress response. Supplementation with the amino acid L tryptophan can lead to blunting of the stress response. Oxytocin results from positive social interactions, and suppresses the HPA axis to enhance health.

Thyroid Function

It has been proposed that the HPA axis can alter thyroid function. Animal studies have demonstrated that chronic stress of laboratory animals can lead to decreased T3 and T4 levels. Despite the lowered T3 and T4 levels, thyrotropin releasing hormone (TRH) levels are not altered by the stressors. There is also data to support that modification of thyroid hormone status can affect the HPA axis. The interactions between the thyroid and the HPA axis, and how to appropriately support them are currently being investigated.

Ovarian Function

There is cross talk between the HPA axis and the hypothalamic pituitary gonadal axis (HPG) affecting ovarian function. Estrogen and testosterone modulate the activity of the HPA axis, and conversely the activation of the HPA axis can affect the proper function of the HPG axis. This can lead to a non cyclic anovulatory ovary which can go on to develop cystic changes. Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women and leads to ovulatory dysfunction. There are two differing type of PCOS, that associated with en elevated body mass index (BMI) and associated normal BMI. Studies have demonstrated that women with PCOS and lower BMI have traits associated with a lowered resistance to stress, higher ACTH levels, reflecting alteration of the HPA axis.

The HPA axis may also have effects on premenstrual syndrome (PMS) in women. Premenstrual syndrome is characterized by mood disorders in the second half (luteal phase) of the menstrual cycle. Studies have shown that women with PMS have an aberrant HPA axis response, and this is regulated through an aberrant response to progesterone.


Endometriosis is a chronic inflammatory condition that is defined by growth of endometrial tissue outside the lining of the uterus. Alterations in the HPA axis and cortisol levels have been found in women with endometriosis.

HPA Axis and Telomeres

Telomeres are the DNA caps at the end of our chromosomes and shortened telomeres have been associated with disease and aging. The HPA axis and its affect on telomere length is a current area of active investigation. Shortened telomere length has been associated with depression and low cortisol levels.


The relationship between stress, and thus the HPA axis, and cardiac disease has been well studied. The relationship between chronic pain and the HPA axis is also being elucidated. Alterations in the gut microbiome have also linked to the HPA axis.

Management of the HPA Axis

  • Lifestyle
  • Restorative exercise
  • Restorative sleep
  • Mindfulness
  • Meditation can reduce stress reactivity and can be of therapeutic benefit in inflammatory conditions characterized by  neurogenic inflammation..  
  • Nutrition
  • Nutritional Supplements for Support

Conclusions and the Future

The importance of the HPA axis in wellness, prevention of disease and treatment of established disease has been advocated in functional medical approaches and is most probably highly important; however its impact is not well studied in traditional medicine.

The impact of the HPA axis should be further investigated in a rigorous scientific fashion. in order to support its importance through a larger medical community.

The plausible and probable importance of the HPA axis in health and wellness further emphasizes the value and necessity of holistic approaches to wellness, disease prevention and disease management,