Antiglucocorticoid

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Antiglucocorticoid
Drug class
Mifepristone structure.svg
Mifepristone, an antiglucocorticoid that is used in the treatment of Cushing's syndrome.
Class identifiers
Synonyms Glucocorticoid antagonist; Cortisol antagonist; Anticorticosteroid
Use Cushing's syndrome, others
Biological target Glucocorticoid receptor
Chemical class Steroids
Legal status
In Wikidata

Antiglucocorticoid drugs are a class of medications that act to reduce the effects of glucocorticoids, primarily cortisol, in the body. [1] They include direct glucocorticoid receptor antagonists such as mifepristone and synthesis inhibitors such as metyrapone, ketoconazole, and aminoglutethimide. They are used to treat Cushing's syndrome. [2]

Contents

These drugs have also been investigated for their potential therapeutic benefits in various psychiatric disorders, particularly depression and psychosis. [3] [4] The rationale behind using antiglucocorticoids in psychiatry stems from the observed dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in many psychiatric conditions, which often manifests as elevated cortisol levels. [4] [5]

Types

There are several types of antiglucocorticoid drugs, including:

  1. Cortisol synthesis inhibitors: These drugs, such as metyrapone, aminoglutethimide, and ketoconazole, work by blocking the production of cortisol in the adrenal glands. [6]
  2. Glucocorticoid receptor antagonists: Mifepristone (RU-486) is the primary example of this class, which directly blocks the action of cortisol at its receptor sites. [3] [6]
  3. Steroid hormones: Dehydroepiandrosterone (DHEA) has been studied for its potential antiglucocorticoid effects. [3]

Therapeutic applications

Cushing's syndrome

Antiglucocorticoid drugs are a treatment option for Cushing's syndrome, a condition characterized by excessive cortisol production. These medications are primarily used in two scenarios: as preoperative treatment to manage symptoms and reduce surgical risks, and as a long-term solution when surgery has failed or is not feasible. [7] [2] The main antiglucocorticoid agents employed in treating Cushing's syndrome include steroidogenesis inhibitors such as metyrapone and ketoconazole, which block cortisol production, and mifepristone (RU-486), which directly antagonizes the glucocorticoid receptor. [2] Metyrapone and ketoconazole are often preferred as first-line pharmacological treatments, either as monotherapy or in combination, due to their efficacy in controlling hypercortisolemia. [2] However, careful monitoring is essential during treatment, as these drugs can potentially cause side effects and, in some cases, lead to adrenal insufficiency. [7] While antiglucocorticoid therapy has shown promise in managing Cushing's syndrome, it is generally considered an adjunctive treatment to surgery, which remains the definitive cure for most cases of the disorder. [2]

Psychiatric disorders

The use of antiglucocorticoid drugs for psychiatric disorders has yielded mixed results. Some studies have shown promise in treating major depression, particularly in cases with psychotic features. [6] However, a Cochrane review of antiglucocorticoid treatments for psychosis found no significant differences in overall psychotic symptoms, positive symptoms, or negative symptoms when compared to placebo. [3]

The mechanism of action for antiglucocorticoid drugs in psychiatric disorders is not fully understood. One hypothesis suggests that these drugs may work by reducing glucocorticoid enhancement of corticotropin-releasing hormone (CRH) action in certain brain regions, such as the central nucleus of the amygdala. [6] Additionally, these drugs may affect glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems. [6]

See also

Related Research Articles

<span class="mw-page-title-main">Cushing's syndrome</span> Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a round red face due to facial plethora, a fat lump between the shoulders, weak muscles, weak bones, acne, and fragile skin that heals poorly. Women may have more hair and irregular menstruation. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.

<span class="mw-page-title-main">Mifepristone</span> Medication

Mifepristone, also known by its developmental code name RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of pregnancy. It is also effective in the second trimester of pregnancy. It is taken by mouth.

<span class="mw-page-title-main">Prednisone</span> Steroid medication

Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and adrenal insufficiency along with other steroids. It is taken by mouth.

<span class="mw-page-title-main">Glucocorticoid</span> Class of corticosteroids

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.

<span class="mw-page-title-main">Adrenal insufficiency</span> Insufficient production of steroid hormones by the adrenal glands

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

<span class="mw-page-title-main">Ketoconazole</span> Antifungal chemical compound

Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.

<span class="mw-page-title-main">Metyrapone</span> Chemical compound

Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). It is part of the steroidogenesis inhibitor class of drugs.

<span class="mw-page-title-main">Methylprednisolone</span> Corticosteroid medication

Methylprednisolone is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. Methylprednisolone and its derivatives can be administered orally or parenterally.

11β-Hydroxysteroid dehydrogenase enzymes catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa, thus regulating the access of glucocorticoids to the steroid receptors.

<span class="mw-page-title-main">Aminoglutethimide</span> Group of stereoisomers

Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. It has also been used by bodybuilders, athletes, and other men for muscle-building and performance- and physique-enhancing purposes. AG is taken by mouth three or four times per day.

Nelson's syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat Cushing's disease. In patients with pre-existing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, loss of adrenal feedback following bilateral adrenalectomy can trigger the rapid growth of the tumor, leading to visual symptoms and hyperpigmentation. The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss from mass compression, as well as invasion into surrounding structures around the pituitary gland.

<span class="mw-page-title-main">Trilostane</span> Chemical compound

Trilostane, sold under the brand name Vetoryl among others, is a medication which has been used in the treatment of Cushing's syndrome, Conn's syndrome, and postmenopausal breast cancer in humans. It was withdrawn for use in humans in the United States in the 1990s but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs. It is taken by mouth.

Critical illness–related corticosteroid insufficiency is a form of adrenal insufficiency in critically ill patients who have blood corticosteroid levels which are inadequate for the severe stress response they experience. Combined with decreased glucocorticoid receptor sensitivity and tissue response to corticosteroids, this adrenal insufficiency constitutes a negative prognostic factor for intensive care patients.

Steroid dementia syndrome describes the signs and symptoms of hippocampal and prefrontal cortical dysfunction, such as deficits in memory, attention, and executive function, induced by glucocorticoids. Dementia-like symptoms have been found in some individuals who have been exposed to glucocorticoid medication, often dispensed in the form of asthma, arthritis, and anti-inflammatory steroid medications. The condition reverses, but not always completely, within months after steroid treatment is stopped.

A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others. By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Amphenone B</span> Chemical compound

Amphenone B, or simply amphenone, also known as 3,3-bis(p-aminophenyl)butan-2-one, is an inhibitor of steroid hormone and thyroid hormone biosynthesis which was never marketed but has been used as a tool in scientific research to study corticosteroids and the adrenal glands. It acts as competitive inhibitor of 11β-hydroxylase, 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, and 3β-hydroxysteroid dehydrogenase, as well as of cholesterol side-chain cleavage enzyme, thereby inhibiting the production of steroid hormones including glucocorticoids, mineralocorticoids, androgens, and estrogens. In addition, amphenone B inhibits the production of thyroxine by a thiouracil-like mechanism, specifically via inhibition of organic binding of iodine and uptake of iodide by the thyroid gland.

An anticorticotropin, or anticorticotrophin, is a drug which opposes the actions of corticotropin-releasing hormone (CRH) and/or adrenocorticotropic hormone (ACTH) in relation to their stimulatory effects on the adrenal glands, or which otherwise suppresses steroid hormone production in the adrenal glands. It can be said to have anticorticotropic effects, and is used to treat Cushing's syndrome, prostate cancer, hyperandrogenism, and other conditions.

<span class="mw-page-title-main">Generalized glucocorticoid resistance</span> Medical condition

Generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic disorder that can run in families or be sporadic. It is characterized by partial or generalized target-tissue insensitivity to glucocorticoids.

<span class="mw-page-title-main">Adrenalism</span>

Adrenalism describes the condition of an excessive or substandard secretion of hormones related to the adrenal glands, which are found directly superior to the kidneys. Adrenalism can be further distinguished as hyperadrenalism, referring to the excessive secretion of hormones, and hypoadrenalism, referring to the insufficient secretion of hormones.

References

  1. Muller C, Hennebert O, Morfin R (July 2006). "The native anti-glucocorticoid paradigm". The Journal of Steroid Biochemistry and Molecular Biology. 100 (1–3): 95–105. doi:10.1016/j.jsbmb.2006.03.001. PMID   16713254.
  2. 1 2 3 4 5 Dang CN, Trainer P (November 2007). "Pharmacological management of Cushing's syndrome: an update". Arquivos Brasileiros de Endocrinologia e Metabologia. 51 (8): 1339–48. doi:10.1590/s0004-27302007000800020. PMID   18209872.
  3. 1 2 3 4 Garner B, Phillips LJ, Bendall S, Hetrick SE (January 2016). "Antiglucocorticoid and related treatments for psychosis". The Cochrane Database of Systematic Reviews. 2016 (1): CD006995. doi:10.1002/14651858.CD006995.pub2. PMC   10337649 . PMID   26725721.
  4. 1 2 McIsaac SA, Westrin Å, Young AH (2009). "Antiglucocorticoids in psychiatry". Advances in Psychiatric Treatment. 15 (4): 242–249. doi:10.1192/apt.bp.105.001834.
  5. Strawbridge R, Jamieson A, Hodsoll J, Ferrier IN, McAllister-Williams RH, Powell TR, et al. (February 2021). "The Role of Inflammatory Proteins in Anti-Glucocorticoid Therapy for Treatment-Resistant Depression". Journal of Clinical Medicine. 10 (4): 784. doi: 10.3390/jcm10040784 . PMC   7920038 . PMID   33669254.
  6. 1 2 3 4 5 Kling MA, Coleman VH, Schulkin J (2009). "Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?". Depression and Anxiety. 26 (7): 641–9. doi:10.1002/da.20546. PMC   3640810 . PMID   19133699.
  7. 1 2 Institute of Medicine (US) Committee on Antiprogestins: Assessing the Science (1993). "Chapter 5: Antiglucocorticoid Effects of Antiprogestins.". In Donaldson MS, Dorflinger L, Brown SS, et al. (eds.). Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington (DC): National Academies Press (US).