Adrenocorticotropic Hormone

Adrenocorticotropic hormone (ACTH) is a peptide hormone produced by the anterior pituitary gland under the regulation of the hypothalamic-pituitary-adrenal (HPA) axis.

 It plays a critical role in stimulating the adrenal cortex to produce glucocorticoids, primarily cortisol from the zona fasciculata, and androgens from the zona reticularis. 

ACTH secretion follows a circadian rhythm, peaking in the early morning and declining in the evening, a pattern crucial for diagnostic testing.  

Dysregulation of ACTH can lead to disorders such as Addison's disease, characterized by insufficient cortisol production, and Cushing's syndrome, involving excess cortisol. 

The hormone's production is stimulated by corticotropin-releasing hormone (CRH) from the hypothalamus and regulated by a negative feedback loop involving glucocorticoids. 

ACTH is also involved in stress response, metabolism, and immune function, making it a vital component of the body's endocrine system.

What is ACTH?  [4.]

Adrenocorticotropic hormone (ACTH) is a hormone produced by the anterior pituitary gland under the regulation of the hypothalamic-pituitary axis.  It stimulates the adrenal cortex to produce glucocorticoids from the zona fasciculata and androgens from the zona reticularis. 

Disorders associated with ACTH dysregulation include Addison's disease, characterized by insufficient cortisol production, and Cushing's syndrome, which involves excess cortisol. 

ACTH's secretion follows a circadian rhythm, peaking in the early morning and dipping in the evening, a pattern significant for diagnostic testing. 

ACTH Physiology

The adrenocorticotropic hormone (ACTH) is a key player in the hypothalamic-pituitary-adrenal (HPA) axis, a complex neuroendocrine system that regulates various physiological processes, including stress response, metabolism, and immune function.

Production and Regulation of ACTH

ACTH is a peptide hormone stimulated by the hypothalamic release of corticotropin-releasing hormone (CRH).  

CRH and ACTH release is inhibited by the presence of glucocorticoids via a negative feedback loop, and stimulated by stress.  [4.] 

ACTH’s Circadian Rhythm  [9.] 

ACTH secretion follows a circadian pattern regulated by the hypothalamic-pituitary-adrenal (HPA) axis, with peaks occurring just before the active phase (daytime in humans). 

This rhythm is influenced by the suprachiasmatic nucleus (SCN), the body's master circadian clock, through autonomic and hormonal signals.  

The SCN coordinates the release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN), which then stimulates ACTH secretion from the pituitary gland. This in turn triggers glucocorticoid release from the adrenal cortex. 

The circadian rhythm of glucocorticoids helps synchronize peripheral clocks throughout the body. 

Stress can modulate this rhythm through feedback mechanisms involving glucocorticoids, which regulate ACTH release.  

Local adrenal clocks also play a role in regulating glucocorticoid production and sensitivity to ACTH. 

Disruptions in these circadian rhythms can affect immune function and overall health, highlighting the importance of maintaining regular circadian patterns for optimal HPA axis function and immune response.

Functions of ACTH in the Body

The functions of ACTH include:  [5.] 

Cortisol Synthesis and Secretion:

• ACTH binds to melanocortin 2 receptors (MC2R) on adrenal zona fasciculata cells, stimulating cortisol production.

• It increases the number of low-density lipoprotein (LDL) receptors and facilitates the transfer of cholesterol into mitochondria, initiating cortisol synthesis.

• ACTH influences multiple steps in the steroidogenic pathway, including the conversion of cholesterol to pregnenolone, a precursor for cortisol.

Circadian Regulation:

• ACTH secretion follows a circadian rhythm, influenced by the suprachiasmatic nucleus (SCN) via the hypothalamic-pituitary-adrenal (HPA) axis and adrenal clocks.

• This rhythm helps in maintaining the daily cycle of cortisol levels, peaking just before the active phase.

Adrenal Growth and Function:

• ACTH stimulates the production of factors like vascular endothelial growth factor (VEGF) and epoxy-eicosa-trienoic acids (EETs), promoting adrenal growth and blood flow.

• Chronic exposure to high levels of ACTH can lead to adrenal hyperplasia, nodules, and neoplasia.

Mineralocorticoid Regulation:

• While ACTH mainly regulates cortisol, it also has a secondary role in aldosterone production by the zona glomerulosa of the adrenal cortex.

Androgen Production:

• ACTH influences the production of weak adrenal androgens in the zona reticularis, although its role is minor compared to other regulators like angiotensin II.

‍Adipocyte Function:

• ACTH affects intra-adrenal and peri-adrenal adipocytes, modulating corticosteroid production and influencing metabolic processes.

Immune System Modulation:

• ACTH can impact the immune system by interacting with melanocortin receptors on immune cells, affecting inflammation and immune responses.

Regulation of Gene Expression:

• ACTH upregulates the expression of genes involved in steroidogenesis, such as those encoding steroid hydroxylases and dehydrogenases.

• It influences the expression of the melanocortin 2 receptor (MC2R) and its accessory protein (MRAP), which are crucial for ACTH's action on adrenal cells.

Response to Stress:

• ACTH plays a pivotal role in the body's response to stress, ensuring the appropriate release of cortisol to manage and adapt to stressors.

Stimulation of Melanocytes:

• ACTH can bind to melanocortin-1 receptors (MC1R) expressed on melanocytes, the pigment-producing cells in the skin which increases melanin synthesis and enhances melanogenic enzyme activity.  [11.] 

ACTH Levels and Normal Range

Establishing accurate reference ranges for ACTH levels is crucial for the proper interpretation of test results and the diagnosis of various endocrine disorders.

Diseases Associated with Altered ACTH Levels

Addison’s Disease  [3., 12.]

Addison's disease, also known as primary adrenal insufficiency, is a condition characterized by the inability of the adrenal glands to produce sufficient amounts of cortisol and, in some cases, aldosterone. 

Addison’s disease is primarily caused by autoimmune destruction of the adrenal glands (although, more broadly, primary adrenal insufficiency can be caused by congenital adrenal hyperplasia; this condition may also cause elevated ACTH levels).  

In some cases Addison’s disease may be caused by other diseases or conditions.  [3.] 

Addison’s disease is directly related to the levels of adrenocorticotropic hormone (ACTH) in the body.

In Addison's disease, the adrenal glands are damaged or dysfunctional, leading to a deficiency in the production of cortisol and, sometimes, aldosterone.  The lack of cortisol production by the adrenal glands causes a disruption in the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis.

Normally, when cortisol levels are high, it signals the hypothalamus and pituitary gland to decrease the production of ACTH.  However, in Addison's disease, the low cortisol levels fail to suppress ACTH production.

As a result, the pituitary gland continues to release high levels of ACTH in an attempt to stimulate the impaired adrenal glands to produce more cortisol.

Elevated ACTH levels are a characteristic finding in Addison's disease and are used as a diagnostic marker for the condition.

ACTH levels in Addison's disease can be extremely high, often several times the normal range, due to the lack of negative feedback from cortisol.

Measuring ACTH levels, along with cortisol levels and other tests, helps differentiate Addison's disease (primary adrenal insufficiency) from other forms of adrenal insufficiency, such as secondary or tertiary adrenal insufficiency, which involve problems with the pituitary gland or hypothalamus, respectively.

The main symptoms of Addison's disease include:  [13.] 

• Fatigue and weakness - This is often one of the earliest and most common symptoms as cortisol helps regulate energy levels.

• Weight loss and decreased appetite - Due to the imbalance of hormones like cortisol that regulate metabolism.

• Darkening of skin (hyperpigmentation) - This can cause tanned or darkened patches of skin, particularly in skin folds, scars, and areas that get more friction or sun exposure. It occurs due to excess production of melanin as the body tries to compensate for lack of cortisol.

• Low blood pressure (hypotension) - Aldosterone deficiency leads to sodium loss and dehydration, causing low blood pressure. This can cause dizziness, lightheadedness or fainting upon standing.

• Salt cravings - The body tries to conserve sodium due to aldosterone deficiency, leading to salt cravings.

• Nausea, vomiting, abdominal pain - Gastrointestinal symptoms are common.

• Muscle cramps, joint pain - Due to electrolyte imbalances like low sodium and high potassium levels.

• Irritability, depression - Hormonal imbalances can affect mood and mental state.

• Low blood sugar (hypoglycemia) - Caused by lack of glucocorticoids like cortisol that regulate blood sugar.

In women, irregular menstrual periods and loss of libido can also occur due to hormonal changes. In acute adrenal crisis, symptoms like severe abdominal pain, extreme weakness, low blood pressure and even shock can develop, requiring emergency treatment.

Cushing’s Syndrome and Cushing’s Disease  [7., 10.]

Cushing’s syndrome and Cushing’s disease are associated with increased cortisol levels.  

The main difference between Cushing's syndrome and Cushing's disease is the underlying cause of excess cortisol production.

In Cushing’s syndrome, increased cortisol may or may not be caused by elevated ACTH.  In contrast, Cushing’s disease always involves increased ACTH levels causing elevated cortisol levels.

Cushing's syndrome refers to the general state of having excessive levels of the hormone cortisol in the body, regardless of the cause.  It can be caused by various factors, including:

• Taking glucocorticoid medications like prednisone for an extended period

• Adrenal gland tumors producing excess cortisol

• Certain types of cancers producing ACTH, which stimulates cortisol production

Cushing's disease, on the other hand, is a specific type of Cushing's syndrome caused by a pituitary adenoma (benign tumor) that secretes excess adrenocorticotropic hormone (ACTH). This excess ACTH then stimulates the adrenal glands to produce excessive cortisol.

The main symptoms of Cushing's disease and Cushing's syndrome are:

• Weight gain - This often occurs around the trunk, face (causing a rounded "moon" face), and upper back (creating a "buffalo hump")

• Skin changes:

• Thin, fragile skin that bruises easily

• Purple or reddish stretch marks on the abdomen, thighs, breasts and arms

• Acne or facial hair growth in women

• Muscle weakness and loss of muscle mass, especially in the arms and legs

• High blood pressure (hypertension)

• High blood sugar levels or diabetes

• Mood and mental changes:

• Depression, anxiety or irritability

• Problems with memory and concentration

• Irregular or absent menstrual periods in women

• Decreased libido and fertility in men, possibly erectile dysfunction

• Osteoporosis (bone loss) which increases fracture risk

• Fatigue and disrupted sleep patterns

• Headaches

• Increased thirst and frequent urination

Other symptoms in children include:

• Stunted growth

• Weight gain around the trunk and face

The symptoms are the same for both Cushing's disease (caused by a pituitary tumor producing excess ACTH) and Cushing's syndrome (excess cortisol from any cause). 

However, Cushing's disease often leads to more severe symptoms due to the higher cortisol levels produced.

Early diagnosis is important, as prolonged exposure to high cortisol levels can lead to serious complications like diabetes, hypertension, osteoporosis, and cardiovascular disease if left untreated.

ACTH Testing and Related Biomarkers

ACTH Blood Test, Sample Collection and Preparation

The ACTH test assesses the level of ACTH present in an individual’s bloodstream.  Sample collection requires a venipuncture.  Often, samples are collected earlier in the day.

It is important to consult with the ordering provider prior to sample collection as certain medications and supplements may need to be avoided beforehand.

ACTH Stimulation Test  [2.] 

The ACTH stimulation test, also known as the cosyntropin stimulation test, is a widely used diagnostic tool for evaluating adrenal function. 

It requires two blood samples to assess cortisol levels, one before the administration of synthetic ACTH (cosyntropin), and the second sample 60 minutes after administration of the cosyntropin.   It is best performed early in the morning.

This test helps assess the ability of the adrenal glands to produce cortisol in response to ACTH stimulation.

Other Tests Related to ACTH and HPA Axis Evaluation

In addition to the ACTH stimulation test, several other tests are used to evaluate the HPA axis and related conditions. 

These include the dexamethasone suppression test, which assesses the negative feedback mechanism of the HPA axis, and the corticotropin-releasing hormone (CRH) test, which evaluates the pituitary's ability to secrete ACTH as well as the adrenal gland’s ability to secrete cortisol in response to CRH stimulation.  [6., 8.]

Interpretation of ACTH Test Results

Optimal Levels of ACTH

Optimal ACTH levels should not be too high or too low, as either scenario could indicate a pathological process.

Blood samples should be drawn earlier in the morning to assess highest levels.  

One laboratory reports optimal levels of ACTH between 7.2−63.3 pg/mL (for samples collected between 7–10 AM)  [2.] 

High ACTH Levels and Associated Conditions

Elevated ACTH levels can be seen in conditions such as Cushing's disease and ectopic ACTH syndrome.  

Cushing's disease is caused by excessive ACTH production from a pituitary adenoma, leading to increased cortisol secretion from the adrenal glands. 

Ectopic ACTH syndrome, on the other hand, is characterized by the production of ACTH by non-pituitary tumors, resulting in excessive cortisol production and associated clinical manifestations.

Low ACTH Levels and Associated Conditions

Low ACTH levels can be indicative of several conditions including glucocorticoid use, cortisol-secreting tumors, and pituitary disorders. 

FAQ: ACTH (Adrenocorticotropic Hormone)

What is ACTH?

ACTH (Adrenocorticotropic Hormone) is a hormone produced by the pituitary gland.  It stimulates the adrenal glands to release cortisol, a hormone that helps the body respond to stress, maintain blood pressure, and regulate metabolism.

What does ACTH do?

ACTH plays a crucial role in stimulating the adrenal glands to produce and release cortisol. Cortisol is essential for various bodily functions, including the stress response, immune function, and maintaining blood sugar levels.

ACTH also has other roles including stimulating androgen release, promoting proper immune function, and others.  

What is the ACTH hormone?

The ACTH hormone, or adrenocorticotropic hormone, is a peptide hormone produced by the anterior pituitary gland that regulates the production of cortisol from the adrenal cortex.

What is an ACTH plasma test?

An ACTH plasma test measures the level of ACTH in the blood.  It helps diagnose problems with the adrenal glands or pituitary gland.

What is an ACTH blood test?

An ACTH blood test measures the concentration of ACTH in the blood to evaluate how well the pituitary and adrenal glands are functioning.

What is an ACTH stimulation test?

The ACTH stimulation test is used to assess the function of the adrenal glands by measuring the cortisol response to an injection of synthetic ACTH via a blood test taken before and after administration of ACTH.  

What is considered low ACTH levels?

Low ACTH levels can indicate conditions such as secondary adrenal insufficiency or pituitary gland disorders. Generally, levels below the normal range for adults (roughly 10-60 pg/mL) may be considered low, but this can vary based on the laboratory and specific circumstances.

What is considered high ACTH levels?

High ACTH levels can indicate conditions such as Cushing's disease, ectopic ACTH syndrome, or primary adrenal insufficiency (Addison's disease).  Levels above the normal range for adults (roughly 10-60 pg/mL) may be considered high.

What is the ACTH normal range?

The normal range for ACTH levels in adults typically falls between about 10-60 pg/mL, but this range can vary depending on the laboratory and the time of day the test is performed.

What are the symptoms of low ACTH levels?

Low ACTH levels that cause low cortisol levels generally manifest as symptoms of low cortisol.  These may include fatigue, muscle weakness, weight loss, low blood pressure and blood sugar, nausea and vomiting, and others.  

What are the symptoms of high ACTH levels?

High ACTH symptoms may also correlate with high cortisol levels and may include weight gain, particularly around the abdomen and face, high blood pressure, muscle weakness, and high blood sugar levels.

Which diseases is the hormone ACTH most affected by?

The hormone ACTH is most affected by diseases such as Addison's disease (primary adrenal insufficiency), Cushing's disease (pituitary adenomas producing excess ACTH), and ectopic ACTH syndrome (non-pituitary tumors producing ACTH).

How to increase ACTH naturally?

To increase ACTH naturally, focus on maintaining a healthy lifestyle, including:

• Stress management: Practicing stress-reducing techniques like meditation and yoga.

• Balanced diet: Eating a nutrient-rich diet to support overall endocrine health.

• Regular exercise: Engaging in regular physical activity to help maintain hormone balance.

• Adequate sleep: Ensuring sufficient rest and sleep to support hormonal regulation.

Where can I find more information about ACTH and related conditions?

For more information about ACTH and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and treatment options.

• Scientific literature: Research articles and reviews on ACTH and endocrine health.

• Reputable health organizations: Websites of organizations such as the National Institutes of Health (NIH) and the Endocrine Society.

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