Physiology, Adrenocorticotropic Hormone (ACTH)


Article Author:
Mary Allen


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Sandeep Sharma


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Updated:
3/3/2019 9:36:23 AM

Introduction

Adrenocorticotropic hormone (ACTH) is a tropic hormone produced by the anterior pituitary. The hypothalamic-pituitary axis controls it. ACTH regulates cortisol and androgen production. Diseases associated with ACTH include Addison disease, Cushing syndrome and Cushing disease.[1]

Cellular

Pro-opiomelanocortin (POMC) gives rise to ACTH and melanocyte-stimulating hormone (MSH). This association is clinically important for Addison disease.

ACTH receptors are in the adrenal cortex, in particular, the zona fasciculata and zona reticularis. The receptors are G protein-coupled receptors thus stimulating adenylyl cyclase. This leads to an increase in intracellular cAMP and activation of protein kinase A.[2]

Organ Systems Involved

Hypothalamic-Pituitary Axis

  • The anterior pituitary produces ACTH. It is considered a tropic hormone. Tropic hormones indirectly affect target cells by first stimulating other endocrine glands. Corticotropin-releasing hormone (CRH) is released from the hypothalamus which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH then acts on its target organ, the adrenal cortex.

Adrenal Cortex

  • The adrenal cortex secretes glucocorticoids from the zona fasciculata and androgens from the zona reticularis.  The secretion of glucocorticoids provides a negative feedback loop for inhibiting the release of CRH and ACTH from the hypothalamus and anterior pituitary, respectively. Stress stimulates the release of ACTH.

Memory tool for secretory products of Adrenal Cortex

  • “The deeper you go, the sweeter you get.”
  • Glomerolusa: Salt (Mineralocorticoids)
  • Fasciculata: Sugar (Cortisol)
  • Retcularis: Sex (Androgens)[3][4]

Function

Glucocorticoids

Metabolism

  •   Hyperglycemia
  •   Catabolism of proteins
  •   Lipolysis
  •   Bone resorption

Immunosuppression

Androgens

  • Primarily dehydroepiandrosterone (DHEA); DHEA is an intermediate male sex steroid. It will be for further synthesis of androgens.
  • Anabolic effects on muscle and bones
  • For men: stimulation of spermatogenesis

Mechanism

CRH is released from the hypothalamus. CRH stimulates the anterior pituitary to release ACTH. ACTH acts on the adrenal cortex to release cortisol and androgens. The increase in cortisol provides a negative feedback system to then decrease the amount of CRH released from the hypothalamus.

ACTH works on G protein-coupled receptors on extracellular membranes on zona fasciculata and zona reticularis of the adrenal cortex. cAMP is the secondary messenger system. Activation of the g-couple receptor activates adenylyl cyclase, thus increase cAMP production.

ACTH plays a role in glucose metabolism and immune function.

The circadian rhythm influences cortisol secretion. The highest levels of cortisol are seen in the early morning, and the lowest levels are in the evening. This concept is important for diagnostic testing.[5]

Pathophysiology

Pathophysiology associated with ACTH can stem from 3 different mechanisms. Issues can be with the pituitary, adrenals, or ectopic secretion.

The pituitary can be hypofunctioning or hyperfunctioning leading to either a decrease or increase, respectively, in ACTH. Pituitary insufficiency is usually the result of an adenoma that destroys the gland. It can also be caused by pituitary apoplexy, a sudden hemorrhage into a pituitary tumor causing sudden loss of ACTH. Sheehan syndrome is a less common cause of pituitary insufficiency. It is a pituitary infarct since after massive blood loss during childbirth.

The adrenal can also be hypofunctioning or hyperfunctioning. Diseases associated with the adrenals include Addison and Cushing.

Ectopic secretion refers the production of a hormone outside of its normal physiology mechanism. Benign or malignant tumor secrete hormone. Normal feedback loop mechanisms do not control the production of the hormone. Cushing syndrome is associated with ectopic ACTH production.[6][7]

Clinical Significance

Addison Disease

Addison disease involves the autoimmune destruction of all 3 layers of the adrenal cortex, which leads to decrease productions of mineralocorticoids, glucocorticoids, and steroids. Other causes of destruction include congenital enzyme deficiencies, tuberculosis, AIDS, and metastasis.

Patient Presentation

  • Symptoms include fatigue, weakness, weight loss, nausea, and vomiting. The physical exam is unique for Addison disease. Due to the lack of negative feedback from the loss of glucocorticoids, CRH and ACTH are continuously stimulated. As mentioned before, ACTH is a byproduct of POMC. Another byproduct of POMC is melanocyte-stimulating hormone (MHC). Both ACTH and MHC will be increased. The increase in MHC will lead to hyperpigmentation. The hyperpigmentation is classically seen in palmar creases and mucosal membranes of the mouth. The patient will also experience hypotension due to loss of mineralocorticoids. Please refer to “Aldosterone” to review this topic.

Labs

  • The loss of mineralocorticoids will lead to loss of aldosterone causing hyponatremia and hyperkalemia. There will be a metabolic acidosis with a normal anion gap. The serum renin will be increased from lack of aldosterone.
  • The etiology of hypercortisolism will determine the level of ACTH. A primary etiology includes issues with the adrenal cortex. The loss of cortisol production from the adrenal cortex will lead to an increase in ACTH from loss of negative feedback.

Diagnostic Testing

  •  An ACTH stimulation is a confirmatory test. Exogenous ACTH is administrated while measuring the levels of serum cortisol before administration and 30 minutes after. For a positive result, serum cortisol levels will remain low after exogenous ACTH. This is because the adrenal cortex is unable to produce cortisol.

Treatment

  • Replace glucocorticoids via hydrocortisone. It is essential to increase the dosage of glucocorticoids during times of stress, such as illness, surgery, and trauma to avoid an adrenal crisis.
  • Replace mineralocorticoids via dehydroepiandrosterone (DHEA) for those that experience decreased libido.
  • Please see “Addison Disease” for further information[8][9][8]

Hypercortisolism

Hypercortisolism has many different etiologies, all with similar patient presentations. Cortisol is a necessary hormone that influences glucose metabolism and immune function. Etiology include exogenous glucocorticoid use, increased adrenal production of cortisol, increased pituitary production of ACTH, or ectopic production of ACTH.

Patient Presentation

  • No matter the etiology, patients with hypercortisolism present with similar symptoms. Symptoms include insulin resistance and possibly overt diabetes mellitus, dyslipidemia due to altered glucose metabolism. The increase in androgen leads to acne and hirsutism in females. There is a change in fat distribution which is seen as central obesity, “moon facies” and “buffalo hump.” Abdominal striae are commonly seen. Patients are at an increased risk of infection and delayed wound healing. Also, avascular necrosis of the femoral head is more likely to occur. Patients are at elevated risk for developing osteopenia and osteoporosis.

Labs

  • Hyperglycemia
  • Hyperlipidemia
  • Hypernatremia
  • Hypokalemia
  • Metabolic alkalosis

Etiologies

  • It is essential to first rule out exogenous corticosteroid use before considering endogenous etiologies of hypercortisolism. Prolonged exogenous use of glucocorticoids is the most common cause of hypercortisolism. Patients with inflammatory conditions such as rheumatoid arthritis commonly use glucocorticoids.
  • Of endogenous hypercortisolism, there are 3 main types. Primary hypercortisolism is known as Cushing syndrome. It is the autonomous overproduction of cortisol by the adrenal gland. Common causes include adrenal adenoma, adrenal carcinoma, and adrenal hyperplasia.
  • Secondary hypercortisolism is due to increased ACTH production, which leads to an increase in cortisol. Secondary hypercortisolism is subdivided into 2 categories: pituitary ATCH production versus ectopic ATCH production. An adenoma commonly causes an increase in pituitary ACTH production. Since the adenoma is located within the pituitary, ACTH production will respond to the hypothalamic-pituitary axis. Ectopic ATCH production is due to a paraneoplastic syndrome. Paraneoplastic syndromes are tumors that secrete active hormone. The most common cancers that secrete ACTH are small cell lung cancer and renal cell carcinoma. Since the secretion of ACTH is produced outside the hypothalamic-pituitary axis, ACTH will not respond to normal feedback mechanism. This is of important note for diagnosis.
  • Confusion may surround the naming of different etiologies of hypercortisolism. For this reason, they are listed here. Primary hypercortisolism, an adrenal issue, is also known as Cushing syndrome. A pituitary adenoma is known as Cushing disease. Exogenous use of corticosteroids may also be referred to as Cushing syndrome.

Diagnostic Testing

  • Once it is established the patient is not using exogenous glucocorticoids, begin by with screening test. Screening test includes 24-hour urine cortisol level, morning serum cortisol level after low-dose dexamethasone, and midnight serum or salivary cortisol level. An increased cortisol level indicates a positive test. Cortisol is influenced by the circadian rhythm, which is why these screening mechanisms work. Its lowest level will be in the evening, with its peak in the morning.
  • After a positive screening test, the next step is to determine the etiology. To begin, obtain a serum ACTH level. If the ACTH level is low, the etiology is likely primary as the adrenal cortex is overproducing cortisol and thus inhibiting the release of ACTH. If the ACTH is high, the etiology is likely secondary.
  • If the secondary hypercortisolism is suspected, testing must be done to differentiate between a pituitary cause or an ectopic cause. A high-dose, typically 8 mg, dexamethasone-suppression test is done. A pituitary adenoma will still respond to the hypothalamic-pituitary axis; however, it needs more feedback to do so. Therefore, with a high-dose suppression test, the production of ACTH will decrease leading to a decrease in cortisol. Ectopic production of ACTH is not within the axis and will not respond to feedback mechanisms. Therefore, there will be no change in cortisol after a high-dose suppression test. A CRH-stimulation test can be done in place of the high-dose dexamethasone suppression test. Recall that CRH is released from the hypothalamus to stimulate the pituitary to secrete ACTH. If there is a further increase in ACTH and cortisol, the etiology is likely to be a pituitary adenoma. If there is no change in the levels of ACTH and cortisol, the etiology is likely to be ectopic.

Imaging

  • It is important to first identify the possible etiology of hypercortisolism via the hormonal test listed above before imaging. Patients may have adrenal incidentalomas which do not need to be removed or active microadenomas that are not detected by scans. For primary hypercortisolism, obtain imaging of abdomen for adrenal tumors. For Cushing disease, obtain imaging of brain for pituitary adenoma. For ectopic etiologies, obtain imaging for chest for small cell carcinoma and abdomen for renal cell carcinoma

Treatment

  • For patients experiencing symptoms with exogenous corticosteroid use, clinical correlation must be used to access if the patient can be discontinued from treatment. If so, taper glucocorticoids to avoid adrenal insufficiency.
  • For endogenous etiologies, surgical therapy is the first line. If inoperable, begin drugs that suppress cortisol synthesis, such as ketoconazole, cabergoline, pasireotide[10]

Infantile Spasms (IS): West Syndrome

Brief Overview

  • The age of onset for infantile spasms is typically younger than one year old. It is rare for IS to occur after 18 months. Spasms include sudden, symmetric, synchronous spasms of neck, trunk, and extremities. Contraction of the abdominal muscle may be severe enough to cause the torso to jackknife at the waist. An EEG is the diagnostic test of choice. The EEG will show pathognomonic hypsarrhythmia. Developmental delay is common in up to 85% of patients. Mortality for children is poor, with rates of 3% to 30%.

Treatment

  • The first-line treatment for IS is ACTH. The role of ACTH in this disease process is unknown. It is thought that patients with IS might have adrenal suppression or that corticotropin may have anticonvulsant effects.[11]

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Physiology, Adrenocorticotropic Hormone (ACTH) - Questions

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Which is not true regarding the normal physiology of the hypothalamus, pituitary, and adrenal glands?



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Which of the following inhibits pituitary secretion of adrenocorticotropic hormone (ACTH)?



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Adrenocorticotropic hormone is most effective in stimulating which of the following secretions?



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Which hormone, in excess, causes Cushing disease, should be collected on ice and stored frozen?



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A 65-year-old male undergoes an high-dose dexamethasone suppression test. Morning cortisol levels remain elevated. What is the common likely cause of his hypercortisolism?



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After a positive screening test for hypercortisolism, a patient undergoes a high-dose dexamethasone suppression test. Morning cortisol level is 70% lower than the pre-test. Where in the body should imaging be localized?



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Physiology, Adrenocorticotropic Hormone (ACTH) - References

References

Adrenocorticotropic hormone for the treatment of West Syndrome in children., Shumiloff NA,Lam WM,Manasco KB,, The Annals of pharmacotherapy, 2013 May     [PubMed]
Approach to the patient with possible Cushing's syndrome., Boscaro M,Arnaldi G,, The Journal of clinical endocrinology and metabolism, 2009 Sep     [PubMed]
Cushing's syndrome: update on signs, symptoms and biochemical screening., Nieman LK,, European journal of endocrinology, 2015 Oct     [PubMed]
Addison's disease., Sarkar SB,Sarkar S,Ghosh S,Bandyopadhyay S,, Contemporary clinical dentistry, 2012 Oct     [PubMed]
Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism., El Ghorayeb N,Bourdeau I,Lacroix A,, Frontiers in endocrinology, 2016     [PubMed]
Impact of ACTH Signaling on Transcriptional Regulation of Steroidogenic Genes., Ruggiero C,Lalli E,, Frontiers in endocrinology, 2016     [PubMed]
Houngbadji MSTS,Niang B,Boiro D,Mbaye A,Seck A,Ndongo AA,Ly ID,Ndiaye O, [Adrenocorticotropic hormone (ACTH) insensitivity syndrome: about a case]. The Pan African medical journal. 2018;     [PubMed]
Patti G,Guzzeti C,Di Iorgi N,Maria Allegri AE,Napoli F,Loche S,Maghnie M, Central adrenal insufficiency in children and adolescents. Best practice     [PubMed]
Fredette ME,Topor LS, Case 3: Emesis and Oral Hyperpigmentation in a 17-year-old Girl. Pediatrics in review. 2018 Aug;     [PubMed]
Miller WL, The Hypothalamic-Pituitary-Adrenal Axis: A Brief History. Hormone research in paediatrics. 2018;     [PubMed]
Hsieh DT,Jennesson MM,Thiele EA, Epileptic spasms in tuberous sclerosis complex. Epilepsy research. 2013 Sep;     [PubMed]

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