Your anterior pituitary gland lies at the base of your brain and produces many important hormones that help to orchestrate many aspects of the body’s endocrine system. One of these hormones is adrenocorticotropic hormone (ACTH), a crucial player in the body’s response to stress. 

ACTH signals to your adrenal glands to release hormones, including cortisol, a key glucocorticoid hormone that helps to regulate your body's response to stress, influences blood pressure, and impacts your sleep-wake cycle. Understanding how ACTH functions to impact the body, how this hormone is regulated, and its implications in health and disease can help with unraveling the complexities of hormonal imbalances and various health issues.

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What is ACTH Hormone?

ACTH is a peptide hormone that is made by the corticotroph cells of the anterior pituitary gland. ACTH is a key signaling hormone that helps to coordinate the hypothalamic-pituitary-adrenal (HPA) axis that helps orchestrate your body’s response to stress.

When the hypothalamus in your brain perceives a threat, it releases corticotropin-releasing hormone (CRH) that signals the anterior pituitary gland to release ACTH. ACTH travels through the bloodstream to the adrenal glands, small endocrine organs located above each kidney. 

ACTH signals the adrenals to release the stress hormone cortisol and androgen sex hormones. 

Through its impacts on cortisol, ACTH influences the metabolism of carbohydrates, protein, and fat metabolism. ACTH stimulates the breakdown of fats to be used as energy, impacts how glucose is utilized, and decreases fatty acid synthesis. In addition, ACTH plays an important role in modulating immune and inflammatory responses.

The Role of ACTH in the Body

ACTH plays many roles in the body, including the following:

Regulation of Cortisol Production

One of the main functions of ACTH is to stimulate the adrenal glands to produce and release cortisol. This glucocorticoid hormone is produced by the adrenal cortex, or outer layer of the adrenal gland, and influences many important body functions.

Cortisol acts on receptors throughout the body, influencing inflammation, immune function, metabolism, gastrointestinal processes, and circadian rhythms. As a key hormone involved in the body’s response to stress, cortisol helps you maintain prolonged alertness and adequate blood pressure and triggers the release of sugar (glucose) from your liver to help you maintain energy to deal with threats. 

ACTH and, therefore, cortisol are normally secreted in a diurnal pattern coordinated with your body’s circadian rhythm or body clock. Cortisol normally peaks early in the morning when you wake and gradually decreases during the day to a low level during sleep. When you are under stress, cortisol levels increase as part of the body’s stress response. 

The body has a negative feedback system to help keep cortisol levels regulated. When cortisol increases in the bloodstream, it provides a negative feedback system to decrease the amount of CRH released from the hypothalamus and, therefore, decreases ACTH release from the pituitary.

ACTH and the Stress Response

ACTH plays a key role in coordinating the adaptive responses that the body enacts to cope with stress. Under stress, the HPA axis is activated with a release of CRH from the hypothalamus, leading to an increase in ACTH release from the anterior pituitary gland. ACTH travels in the bloodstream to the adrenals, where it stimulates an increase in cortisol release.

Cortisol helps to mobilize key resources to deal with stressors by increasing blood pressure, mobilizing energy, and suppressing non-essential functions like digestion and immune responses. During stress, these neuroendocrine changes also influence mood, cognition, and motivation to impact your emotional stress response.

In this way, ACTH is a key regulator of how you adapt to and handle stress. It is an important mediator of the intricately coordinated responses that your body uses to maintain homeostasis during times of stress. 

Disorders Associated with Abnormal ACTH Levels

The following conditions can arise from abnormal ACTH levels:

Conditions Leading to Elevated ACTH Levels

Elevated ACTH levels can result from several causes and generally result in elevations of cortisol that have wide-reaching effects on the body. Causes of elevated ACTH levels include Cushing’s disease, a tumor-producing ectopic adrenocorticotropic hormone, and primary adrenal insufficiency.

Cushing’s disease is one type of Cushing’s syndrome, a hormonal condition that occurs when there is too much cortisol in the body. In Cushing disease, a benign tumor or excess growth (hyperplasia) of the anterior pituitary gland leads to excessive release of ACTH, which signals the adrenal glands to release elevated levels of cortisol into the bloodstream.

Less commonly, a tumor outside of the pituitary gland can release excess ACTH (ectopic adrenocorticotropic hormone tumor). Although rare, medullary carcinoma of the thyroid, benign carcinoid tumors of the lung, islet cell tumors of the pancreas, small cell tumors of the lung, and tumors of the thymus gland can sometimes produce ACTH, causing elevated levels of cortisol.

Another cause of elevated ACTH is primary adrenal insufficiency, such as Addison’s disease. 

This occurs when the adrenals are damaged or malfunctioning and do not produce enough cortisol. This can occur from an autoimmune issue where the immune system creates excess inflammation that targets the adrenal glands or from infections like tuberculosis. With primary adrenal insufficiency, lower-than-expected levels of cortisol send feedback that leads the pituitary to produce excess ACTH to try to stimulate the adrenal glands.

Conditions Associated with Low ACTH Levels

In other conditions, ACTH levels are too low. If low ACTH levels are due to a pituitary gland condition, you usually also have low cortisol. On the other hand, if issues with the adrenal glands are causing low ACTH, cortisol levels are generally elevated. 

Low ACTH levels can occur due to hypopituitarism, which causes secondary adrenal insufficiency. In this rare condition, there is a lack of one or more of the hormones made by the pituitary gland which can include a deficit of ACTH. Low levels of ACTH result in decreased stimulation of the adrenal cortex and low cortisol secretion. This can occur due to damage to the pituitary gland from elevated intracranial pressure, radiation, or surgical injury. 

Unlike Cushing’s disease, Cushing’s syndrome, or elevated cortisol, that occurs from an adrenal tumor or due to long-term use of corticosteroid medications, may result in low ACTH. In these conditions, excess cortisol feeds back to the pituitary gland and suppresses its output of ACTH. 

Managing and Treating ACTH-Related Disorders

With the following options, ACTH-Related disorders can be managed:

Treatment Options for High ACTH Levels

Disorders that result in elevated ACTH levels can significantly disrupt the body's hormonal balance, causing metabolic, cardiovascular, musculoskeletal, and immunological issues. Therefore, it is important to recognize and appropriately manage these conditions to avoid the adverse impacts of high ACTH and cortisol imbalances. 

The management of elevated ACTH varies depending on the underlying cause. Cushing’s disease and tumors that produce ectopic ACTH are usually treated with surgery to remove the pituitary tumor or radiation to shrink the overgrowth. 

In some cases, medications are also used to reduce cortisol production and/or block its effects on target tissues. These can include adrenal steroidogenesis inhibitors to block the synthesis of cortisol like ketoconazole, metyrapone, or mitotane, or medications that reduce ACTH secretion from the pituitary or other tumors like cabergoline or pasireotide.

In Addison’s disease or primary adrenal insufficiency, synthetic versions of cortisol are used to replete deficient hormones. Medications like hydrocortisone are used chronically to replenish cortisol to normal levels and regulate feedback that normalizes ACTH levels. 

Approaches to Manage Low ACTH Levels

Similarly to elevated ACTH levels, the treatment for low ACTH depends on the underlying cause of the imbalance. If low levels of ACTH levels are due to hypopituitarism that causes secondary adrenal insufficiency, hormone replacement of inadequate hormones is used.

 For low ACTH leading to low levels of cortisol, synthetic glucocorticoids, such as hydrocortisone, prednisone, or dexamethasone, are used to restore cortisol levels and regulate metabolism, blood pressure, and responses to stress. 

When primary adrenal insufficiency also impacts levels of the mineralocorticoid aldosterone, additional hormone replacement with mineralocorticoid medications like fludrocortisone may be added to regulate electrolyte levels and blood pressure.

Testing for ACTH Levels

Here is how to test and interpret ACTH levels:

Indications for ACTH Testing

When adrenal or pituitary disorders impacting the HPA axis are suspected, an ACTH test may be used as part of the workup to pinpoint the specific cause of the imbalance. Symptoms like weight changes, especially in the face and abdomen, muscle weakness, loss of appetite, easy bruising, and fatigue may raise suspicion of an issue involving abnormal ACTH levels. 

In addition, ACTH levels can be measured to monitor glucocorticoid replacement therapy to ensure adequate medication levels and sufficient adrenal suppression.

Understanding ACTH Test Results

ACTH levels are usually measured as part of a comprehensive workup that looks at overall symptoms and signs as well as other blood markers like cortisol levels. 

Overall, when both ACTH and cortisol are elevated, this suggests that a pituitary gland tumor or overgrowth may be triggering the adrenal glands to produce too much cortisol. This occurs in Cushing’s disease. In this case, additional testing with imaging scans like an MRI can assess if a pituitary tumor is present to help guide treatment. 

If no tumor or hyperplasia is found in the pituitary gland, imaging of the lungs, pancreas, and/or thyroid gland may be needed to look for tumors producing ectopic ACTH.

When ACTH is elevated but cortisol levels are low, it can indicate the adrenal glands are not functioning as occurs in primary adrenal insufficiency like Addison’s disease. In these cases, the adrenal glands cannot make enough cortisol so the pituitary compensates by making extra ACTH to try to stimulate production.

In cases of Cushing’s syndrome, ACTH is low, but cortisol remains elevated since cortisol is being produced by an adrenal gland tumor or from long-term use of steroid medications. 

If both ACTH and cortisol are low or ACTH is normal while cortisol is low, this is a sign of hypopituitarism causing secondary adrenal insufficiency. When this occurs, the pituitary gland is not making enough ACTH, so the adrenal glands are not stimulated to make enough cortisol and may shrink. 

To help differentiate between these causes of abnormal ACTH levels, additional testing, like an ACTH stimulation test, may be required. In this test, an injection of ACTH is given and cortisol levels are measured afterward. This helps determine if the adrenal glands are responding normally to ACTH stimulation by producing cortisol. 

The Importance of Regular Monitoring

ACTH levels should be monitored over time in patients with known pituitary or adrenal conditions and in those taking certain medications that impact the HPA axis. Regular monitoring and check-ups are important for managing health and maintaining optimal hormonal balance. 

Regularly measuring ACTH and cortisol levels can help with optimizing hormonal replacement therapy and assessing the success of surgery or radiation to remove pituitary or other tumors. This blood testing can guide the adjustment of medication treatment to improve hormonal balance and symptom management.

Changes in ACTH and/or cortisol levels can also be an indicator of disease progression or recurrence. Regular monitoring allows for early detection of disease progression or recurrence and leads to more timely intervention to reduce complications and improve quality of life.

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Key Takeaways

ACTH is a key orchestrator of the HPA axis, influencing the stress response and many physiologic processes including metabolism, blood pressure, and immune function. Through its influence on the adrenal glands’ production of cortisol, ACTH plays a pivotal role in coordinating your body’s adaptive responses to stressors.

When levels of ACTH are out of balance, many health issues can arise. Conditions such as pituitary tumors (Cushing’s disease), adrenal insufficiency, and Cushing's syndrome can result in abnormal levels of ACTH. Depending on the underlying issue, surgery, radiation, and/or medication may be used to bring the body back into hormonal balance. Regular monitoring and targeted interventions are part of a comprehensive and personalized approach to ACTH-related disorders.