In Part 1 of this series on the physiology of stress, I described the evolutionary goals of the stress response and the functions of the sympathetic nervous system that meet these. In this post, we’ll look at the endocrine response to stress.
The Hypothalamic-Pituitary-Adrenal Axis
Mother nature likes redundancy. If one system fails to achieve its goals, backups are essential. In one way, the endocrine system can be thought of as backing up and supporting many of the functions of the nervous system, though this description is an oversimplification. In the case of high stress or survival-type scenarios, the endocrine system both provides support to the sympathetic nervous system and performs additional functions. Three anatomical structures are primarily responsible for the endocrine response to stress: the hypothalamus, pituitary gland, and adrenal glands. These three structures, and their collective response to stress, constitute the hypothalamic-pituitary-adrenal axis, or HPA axis.
The hypothalamus is a small, funnel-shaped structure of the forebrain situated just superior to the pituitary gland. The hypothalamus is responsible for control of the autonomic nervous system and endocrine system. It regulates many primitive functions of the body, such as water metabolism, thermoregulation, and sexual function. It monitors and regulates homeostasis of nearly all the major organs of the body and does this in close coordination with the pituitary gland.
The pituitary gland is about the size of a kidney bean and is attached to the hypothalamus just below it. It has two lobes that release different hormones for different functions, the anterior and posterior lobes. The pituitary is often referred to as the “master gland” because it influences or controls the functions of many other glands and tissues. The organs and tissues affected by the pituitary gland include the liver, kidney, thyroid, adrenals, mammary glands, ovaries and testes. The pituitary exerts control over the activity of the thyroid gland, and, as we’ll see later, the thyroid has direct influence on the metabolic rate of essentially all tissues in the body. Because of this, the pituitary is a pretty big deal.
While the hypothalamus is classified as part of the nervous system, the pituitary gland is a full-fledged endocrine gland. Both the hypothalamus and the pituitary have wide ranging functions across a variety of organ systems, but we’ll restrict our discussion to their roles in the stress response.
Last up are the adrenal glands. The adrenals are a pair of glands attached to the superior surface of the kidneys. They have a pyramidal shape and are about three inches long and a half inch thick. In a sense, each adrenal can be thought of as two separate glands. The outer surface is called the adrenal cortex, and the center is the adrenal medulla. The cortex produces hormones called corticosteroids in response to hormonal stimulus from the pituitary. There are three classes of corticosteroids: mineralocorticoids, glucocorticoids, and sex steroids. Mineralocorticoids regulate fluid and electrolyte balance. Glucocorticoids help regulate the metabolism of glucose and other fuels. Sex steroids regulate sexual development and reproductive function.
How does the HPA axis respond to stress? Any situation we encounter that generates fear or stress, such as a frightening predator, is first identified cognitively in the cerebral cortex of the brain. This information sets off a response by the hypothalamus, which triggers or activates the sympathetic nervous system, setting in motion all of the physiological effects described in the prior post. In addition, the hypothalamus signals the pituitary to initiate a hormone cascade to produce “stress hormones.”
Like a string of dominoes, the hypothalamus starts a chain reaction, first activating the pituitary, then the adrenals. The hypothalamus releases corticotropin-releasing hormone (CRH) directly into the pituitary via a network of blood vessels called the hypophyseal portal system. CRH triggers the release of adrenocorticotropic hormone (ACTH) into the blood by the anterior lobe of the pituitary gland. The target organ of ACTH is the adrenal gland, specifically the adrenal cortex.
In response to ACTH, the adrenal cortex releases hormones called glucocorticoids into the bloodstream. The most important of these is cortisol, which regulates glucose, protein and fat metabolism. Cortisol stimulates fat and protein catabolism (energy-releasing reactions), gluconeogenesis (synthesis of glucose), and the release of fatty acids and glucose into the blood. All these substances serve as fuel for energy to facilitate intense physical activity. As we observed in our discussion of the sympathetic nervous system, the goal here is to dump fuels into the blood so the heart, brain and skeletal muscle have plenty of energy for activity, whether that’s kung fu fighting or all-out sprinting.
The adrenal cortex also produces mineralocorticoids, including aldosterone. Aldosterone is tightly regulated by the endocrine system because of it’s influence on blood volume. Aldosterone stimulates the kidneys to retain sodium and excrete potassium in the urine. Higher sodium in the blood increases blood volume and blood pressure. Higher blood pressure provides more fuel-rich blood to the brain and skeletal muscle with each heart contraction.
This is an example of the redundancy we mentioned earlier. The sympathetic nervous system initiates several mechanisms for increasing blood glucose, blood volume and blood pressure, while the HPA axis amplifies and augments these effects by dumping “stress hormones” into the bloodstream. Because the HPA axis operates via hormonal release, it takes more time to produce its effects. The hypothalamus signals the pituitary, which signals the adrenals to release stress hormones into the blood. These stress hormones then have to travel through the bloodstream to their target organs to take effect. This is a slower system than the sympathetic response, but it’s still very effective.
Other Endocrine Functions
The HPA axis constitutes the endocrine system’s most significant response to stress, but stress triggers additional endocrine activity worth mentioning. The activation of the thyroid by the hypothalamus is of great importance during stressful situations. Under stress, the hypothalamus releases thyroid-stimulating hormone (TSH) into the bloodstream. The thyroid gland, situated along the trachea, is the target organ of TSH. TSH acts on the thyroid to stimulate the release of thyroid hormone. Thyroid hormone refers to two hormones, triiodothyronine (T3) and thyroxine (T4). 98% of thyroid hormone production is T4, though T3 is the more physiologically active of the two. Most T4 is converted to T3 within target cells.
T3 has wide-ranging effects throughout the body. It’s primary function is to increase overall metabolism, or basal metabolic rate, burning more fuel and generating more heat. It increases respiratory rate, heart rate, strength of heartbeat, and oxygen consumption. All these effects work to ensure increased blood and oxygen supply for greater metabolic demand. T3 also accelerates the breakdown of carbohydrates, fats and protein for fuel, continuing our narrative of more fuel available for energy.
(Thyroid hormone also increases appetite, promotes secretion of growth hormone, and promotes the growth of bones, skin, hair, nails and teeth. These functions are not essential in an acute stress response, but the production of T3 is released and regulated during times of calm, not just acute stress.
Another important hormone released in response to stress is vasopressin. Vasopressin, or antidiuretic hormone (ADH), is manufactured by the hypothalamus and released by the pituitary. Vasopressin regulates fluid loss through the urinary tract. By promoting water reabsorption and decreasing perspiration, vasopressin increases blood volume and blood pressure. If stress remains chronically high for an extended period of time, vasopressin can lose its ability to maintain homeostasis and keep blood pressure in a healthy range. In this scenario, increases in stress trigger the release of vasopressin, which increases blood pressure that’s already elevated. This is one of many links between stress and high blood pressure, which is why reducing stress is so critical in treating hypertension.
The effects of the HPA axis, thyroid hormone and vasopressin are categorized as the prolonged effects of stress. This is because hormones released into the bloodstream in this way have half-lives that are hours or even weeks long. That means our bodies can remain in an activated state following a stressful situation for days beyond what is necessary to properly respond to the situation.
Chronic, ongoing stress is not only uncomfortable, it’s unhealthy. The systems described here evolved over millions of years to amp up the body in response to physically dangerous situations. Physical danger still exists in our modern world, but our stress responses are more frequently triggered by situations that call for thoughtful consideration and a reasoned response, not a club or spear.
The most common causes of stress we encounter are cognitive or emotional. Cognitive sources of stress include things like deadlines for work or school, arguments and misunderstandings, job and financial security, and even sports and entertainment. Emotional causes of stress include anger, grief, depression, anxiety and guilt.
Understanding how our bodies respond to stress can help inform our conscious responses to stress. Knowing that a stress response lingers in our bodies and has ongoing effects for hours or days can motivate us to reduce or avoid stressful situations and take proactive steps to reduce overall stress. In future articles, we’ll examine the consequences to health of chronic, long-term stress and explore strategies for managing and reducing stress.