Materiały źródłowe

• #1 Cushing Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470218/

  Cushing syndrome is caused by prolonged exposure to high circulating levels of cortisol. The most common cause of cushingoid features is iatrogenic corticosteroid use, while some herbal preparations can also increase circulating corticosteroid levels leading to Cushing syndrome. Cushing syndrome can be interchangeably called hypercortisolism. ACTH-dependent cortisol excess due to a pituitary adenoma is called Cushing disease, and it is responsible for 80% of endogenous Cushing syndrome. […] Cushing syndrome is caused by prolonged exposure to high circulating levels of cortisol. The most common cause of cushingoid features is iatrogenic corticosteroid use, while some herbal preparations can also increase circulating corticosteroid levels leading to Cushing syndrome. Cushing syndrome can be interchangeably called hypercortisolism. ACTH-dependent cortisol excess due to a pituitary adenoma is called Cushing disease, and it is responsible for 80% of endogenous Cushing syndrome.

• #1 Cushing’s syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Cushing%27s_syndrome

  Cushing’s syndrome is caused by either excessive cortisol-like medication, such as prednisone, or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands. […] Cushing’s disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma (secondary hypercortisolism/hypercorticism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism). This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. […] When Cushing’s syndrome is due to extra ACTH it is known as ectopic Cushing syndrome. […] The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on CRH in the hypothalamus, which decreases the amount of ACTH released from the anterior pituitary gland.

• #1 Cushing’s disease: pathobiology, diagnosis, and management in: Journal of Neurosurgery Volume 126 Issue 2 (2017) Journals

  https://thejns.org/view/journals/j-neurosurg/126/2/article-p404.xml

  Cushing’s syndrome (CS) is caused by prolonged supraphysiological levels of circulating cortisol. Cushing’s disease (CD) is the most common etiology (70%-80% of CS cases) of endogenous CS. It is caused by a pituitary adenoma that secretes adrenocorticotropic hormone (ACTH), which stimulates secretion of cortisol by the adrenal glands. If not effectively treated, CD is associated with hypertension, diabetes, obesity, osteoporosis, vascular disease, and shortened life span. Successful resection of a CD-associated ACTH-secreting pituitary adenoma results in immediate biochemical remission and preservation of pituitary function. Early identification of CD by clinical findings, endocrinological evaluation, and imaging studies is critical for diagnosis and effective surgical management. […] CD is caused by a benign monoclonal pituitary corticotroph adenoma that secretes excessive ACTH, which causes supraphysiological secretion of glucocorticoids from the adrenal glands. The excess circulating cortisol disrupts the normal physiological diurnal variation in cortisol levels and exerts negative feedback inhibition on CRH secretion from the hypothalamus. However, the adenoma itself is relatively resistant to inhibition by endogenous circulating cortisol. Consequently, CD is associated with suppressed secretion of CRH and elevated levels of ACTH in relation to the degree of cortisol production.

• #1 Cushing Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448184/

  The renin-angiotensin-aldosterone system hormone system regulates plasma sodium concentrations as well as arterial blood pressure, which can indirectly lead to hypokalemia. […] Patients with Cushing disease almost always have a pituitary adenoma, often not evident by imaging. However, rare cases may result from diffuse corticotroph cell hyperplasia, even without ectopic secretion of CRH. […] Several genetic mutations are responsible for these adenomas. […] The most common mutation is USP8 (ubiquitin-specific peptidase 8). These mutations lead to abnormal expression of growth factors, which act with ACTH to increase cortisol levels.

• #1 Advances in Molecular Pathophysiology and Targeted Therapy for Cushing’s Disease

  https://www.mdpi.com/2072-6694/15/2/496

  Compared with normal corticotrophs, pituitary corticotroph tumors require higher doses of glucocorticoids to inhibit ACTH secretion. Therefore, corticotroph tumors are considered to have a partial lack of response to glucocorticoid negative feedback. Various factors have been suggested to be involved in this resistance. Corticotroph tumors overexpress heat shock protein 90 (HSP90), leading to disruption of the HSP90 complex, which induces the partial glucocorticoid resistance of corticotroph tumors. […] Cushing’s disease is caused by dysregulation of ACTH synthesis and secretion, due to corticotroph tumors. It is therefore important to understand the regulation of ACTH production and release, and the difference between normal corticotroph cells and corticotroph tumor cells. […] Three main factors are involved in the etiology of Cushing’s disease: tumorigenesis, autonomous ACTH production and secretion, and glucocorticoid resistance. These factors mutually affect each other.

• #1 The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease

  https://www.mdpi.com/1422-0067/21/23/9132

  Based on the response to low-dose DST, one of their most prominent characteristics of ACTHomas is the impaired ACTH suppression by glucocorticoid negative feedback, which further leads to ACTH-dependent hypercortisolemia. The decreased sensitivity to glucocorticoids cannot be explained by the loss-of-function mutations in GR in most cases. […] At the intracellular pre-receptor level, glucocorticoid activity has been shown to be negatively regulated through 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts cortisol into its inactive form, cortisone. Increased expression of 11β-HSD2 has been observed in ACTHomas, and is in turn implicated in inducing glucocorticoid resistance. […] Conclusively, increased expression of 11β-HSD2, HSP90, or TR4, and loss of expression of BRG1 or CABLES1, contribute to the pathogenesis of ACTHomas. This mainly occurs through conceding GR function, which in turn impairs the glucocorticoid negative feedback system.

• #1 New Trends in Treating Cushing’s Disease – touchENDOCRINOLOGY

  https://touchendocrinology.com/pituitary/journal-articles/new-trends-in-treating-cushings-disease/

  This gene codes for a protein with deubiquitinase activity, which rescues proteins such as EGFR from lysosomal degradation. […] Mutated USP8 exerts higher deubiquitinase activity, probably explaining the aberrant EGFR signalling in corticotrophs. […] It is estimated that 16.5% of USP8 wild-type corticotroph adenomas carry BRAF (B-raf proto-oncogene, serine/threonine kinase) mutations encoding p.V600E, resulting in increased MAPK (mitogen-activated protein kinase) activity and subsequent POMC expression. […] A BRAF-kinase inhibitor, vemurafenib, was reasonably evaluated, and it was discovered to suppress ACTH secretion from primary cultures of human corticotroph adenomas harbouring BRAF V600E. […] Heat shock protein 90 (HSP90) is a chaperone protein that induces conformational changes in the glucocorticoid receptor, among others, and affects its transcriptional activity.

• #1 Cushing’s disease | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-41

  Triggering signals leading to Cushing’s disease remain unclear. Oncogenes do not appear to be involved, as somatic mutations are usually not present in corticotroph adenomas cells. Recent studies in mice identified a potential role of loss of function of Brg1 (brahma-related gene 1) and HDAC2 (Histone Deacetylase 2) in the pathogenesis of Cushing’s disease. Both proteins form a complex with the glucocorticoid receptor and the orphan nuclear receptor nuclear growth factor IB (NGFI-B) to repress POMC secretion. […] Transcription factors involved in progenitors proliferation and differentiation during pituitary embryogenesis could also be involved in pituitary tumorigenesis.

• #1 Cushing Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470218/

  There are two main etiologies of Cushing syndrome: endogenous hypercortisolism and exogenous hypercortisolism. Exogenous hypercortisolism, the most common cause of Cushing syndrome, is mostly iatrogenic and results from the prolonged use of glucocorticoids. Endogenous Cushing syndrome results from excessive production of cortisol by adrenal glands and can be ACTH-dependent and ACTH-independent. ACTH-secreting pituitary adenomas (Cushing disease) and ectopic ACTH secretion by neoplasms are responsible for ACTH-dependent Cushing. Adrenal hyperplasia, adenoma, and carcinoma are major causes of ACTH-independent Cushing syndrome. […] Cortisol is a steroid hormone produced by the zona fasciculata of the adrenal cortex. After production the cortisol is carried to different parts of the body by cortisol binding protein, almost 90% of cortisol binds to this (CBG) protein and has a bioavailability of 60% to 100%. Synthetic corticosteroids have varying bioavailability and potency, but all affect similar pathways. It is a catabolic hormone that is released under stressful conditions. The excess of cortisol results in an increased rate of gluconeogenesis, glycogenolysis and increases insulin resistance. Cortisol is a steroid hormone, and it directly affects the transcription and translation of enzyme proteins involved in the metabolism of fats, glycogen, proteins synthesis, and Kreb’s cycle. It promotes the production of free glucose in the body, elevating glucose levels, while simultaneously increasing insulin resistance. The destruction of protein yields amino acids which are used in gluconeogenesis. The prolonged catabolism of proteins causes purplish striae of the torso, osteoporosis, and poor wound healing. All these processes involve collagen which is a three amino-based protein. High cortisol levels also cause immune disruptions; this hormone leads to a decrease in lymphocyte levels and increases the neutrophils. It causes detachment of marginating pool of neutrophils in the bloodstream and increases the circulating neutrophil levels although there is no increased production of the neutrophils. This mechanism explains the typical picture of raised TLC where there is decreased lymphocyte number and increased neutrophils. The corticosteroids mediate the downregulation of NF-kappaB, regulation of AMP kinase, glycogen phosphorylase, superoxide dismutase, and many other enzymes. Cortisol inhibits the production of IL-2, TNF alpha, IFN alpha, and gamma. Decreased IL-2 levels prevent the proliferation of T-lymphocytes.

• #1 Endogenous Cushing Syndrome: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2233083-overview

  ACTH-dependent Cushing syndrome is characterized by elevated ACTH levels. Elevated ACTH levels are usually due to an anterior pituitary tumor, which is classic Cushing disease (60-70%). Nonpituitary ectopic sources of ACTH, such as small-cell lung carcinoma (oat cell carcinoma), carcinoid tumor, medullary thyroid carcinoma, or other neuroendocrine tumors can result in high ACTH levels and sequentially hypercortisolism. […] Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion is associated with a very rare group of cases of Cushing syndrome.

• #1 SciELO Brazil – Unusual causes of Cushing’s syndrome Unusual causes of Cushing’s syndrome

  https://www.scielo.br/j/abem/a/hkTDwN4Xr4SsvpDJ7mjg59d/?lang=en

  Although in the majority of the patients with Cushing’s syndrome (CS), hypercortisolism is due to ACTH hypersecretion by a pituitary tumour or to ectopic ACTH secretion from an extrapituitary neoplastic lesion or to autonomous cortisol secretion by an adrenal tumour, in occasional patients a much rarer entity may be the cause of the syndrome. […] The following unusual forms of CS were identified: (i) ACTH hyperesecretion due to ectopic corticotroph adenomas in the parasellar region or the neurohypophysis, or as part of double adenomas, or gangliocytomas; (ii) ACTH hypersecretion due to ectopic CRH or CRH-like peptide secretion by various neoplasms; (iii) ACTH-independent cortisol hypersecretion from ectopic or bilateral adrenal adenomas; (iv) glucocorticoid hypersensitivity; (v) iatrogenic, due to megestrol administration or to ritonavir and fluticasone co-administration.

• #1 Cushing’s syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Cushing%27s_syndrome

  Strictly, Cushing’s syndrome refers to excess cortisol of any etiology (as syndrome means a group of symptoms). One of the causes of Cushing’s syndrome is a cortisol-secreting adenoma in the cortex of the adrenal gland (primary hypercortisolism/hypercorticism). The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. […] When Cushing’s syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offers equal detection rates.

• #1 Cushing Syndrome – Adrenal Gland Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.11.2.

  Cushing syndrome is a clinical syndrome that includes signs and symptoms resulting from longstanding exposure of tissues to excess glucocorticoids. […] Cushing syndrome is classified based on etiology. […] Endogenous Cushing syndrome results from adrenal overproduction of glucocorticoids. […] Adrenal tumors: Excess cortisol inhibits CRH and ACTH secretion, causing atrophy of the adrenal cortex located outside the tumor capsule and atrophy of the contralateral adrenal gland. […] Bilateral macronodular adrenal hyperplasia is characterized by large multiple nodules sized 1 cm. It is usually sporadic or, less frequently, familial (ARMC5 mutation). Pathophysiology is related to aberrant G protein-coupled receptors activated by atypical stimuli, such as gastric inhibitory peptide, catecholamines, antidiuretic hormone, thyroid-stimulating hormone, luteinizing hormone, angiotensin II, serotonin, and human chorionic gonadotropin.

• #1 Cushing Syndrome – Adrenal Gland Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.11.2.

  Bilateral micronodular adrenal hyperplasia (primary pigmented nodular adrenal disease [PPNAD]) is characterized by nodule diameter 1 cm. It may be sporadic or occur as part of Carney complex (a hereditary autosomal dominant condition associated with abnormalities in various tissues such as cardiac myxoma, lentiginosis, breast ductal adenoma, and testicular tumors).

• #1 Cushing Syndrome: Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/5497-cushing-syndrome

  Cushing syndrome is a condition caused by too much of the hormone cortisol in the body. A tumor typically causes the cortisol levels found in Cushing syndrome. […] Cushing disease is a type of Cushing syndrome. A benign tumor located in the pituitary gland that secretes too much ACTH (adrenocorticotropic hormone) causes Cushing disease. This increases cortisol secretion from the adrenal glands. […] Too much cortisol causes Cushing syndrome. There may be many underlying causes of high cortisol levels, including: Use of glucocorticoid medications. Glucocorticoid medications (for example, prednisone) are used to treat many autoimmune diseases, such as chronic asthma, rheumatoid arthritis, lupus, sarcoidosis and many other diseases that result in chronic inflammation. Chronic treatment with these medications causes iatrogenic or exogenous Cushing syndrome.

• #1 Cushing’s Syndrome – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/cushings-syndrome

  Cushing’s syndrome results from excessive glucocorticoid excretion, which has multi-systemic effects. […] Glucocorticoids induce hyperglycemia via gluconeogenesis and insulin resistance, potentially leading to type 2 diabetes. […] Glucocorticoids also contribute to hypertension by increasing sodium reabsorption and catecholamine sensitivity, leading to vasoconstriction. […] Additionally, glucocorticoids cause skin changes like purple striae, muscle weakness, and osteoporosis by altering collagen, muscle, and calcium metabolism, respectively. […] Cushing’s disease is a form of Cushing’s syndrome caused by an ACTH-secreting pituitary adenoma, leading to elevated ACTH and cortisol levels as well as bilateral adrenal hyperplasia. […] In contrast, a cortisol-secreting adrenal tumor, either an adenoma or carcinoma, results in ACTH-independent Cushing’s syndrome.

• #1 Cushing Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448184/

  Cushing disease is an endocrine disorder characterized by excessive adrenocorticotropic hormone (ACTH) production by the anterior pituitary, which leads to the release of an excess of cortisol from the adrenal glands. […] A pituitary adenoma often causes this, or it results from excess production of corticotropin-releasing hormone (CRH) from the hypothalamus. […] In Cushing disease, the frequency of ACTH production remains the same, but the normal circadian rhythm is lost. The increased plasma ACTH causes bilateral adrenal hyperplasia and a consequent increase in the production of cortisol. Therefore, the normal circadian rhythm of cortisol is also lost. […] Cortisol functions primarily as a glucocorticoid; however, in high concentrations, cortisol can also exhibit mineralocorticoid activity, leading to hypertension and hypokalemia through the renin-angiotensin-aldosterone system.

• #1 cushing | Calgary Guide

  https://calgaryguide.ucalgary.ca/?s=cushing

  Cortisol exerts negative feedback on hypothalamus gonadotropin releasing hormone (GnRH) secretion GnRH LH/FSH estrogen and testosterone production (especially important in females) Infertility, Libido, Irregular Menses […] Cortisol fat breakdown (lipolysis) Selective expression of cortisol receptor on different adipose tissues central, facial, dorsal fat is less broken down than in other areas (mechanism unclear) Combined with cortisol appetite

• #1

  https://link.springer.com/article/10.1007/BF03401535

  Chronic exposure to high glucocorticoid levels in Cushings syndrome (CS) is often associated with alterations in the hemostatic system and the expression of prothrombotic phenotypes. Increased frequency of both atherothrombotic and venous thromboembolic events (VTE) has been reported in patients with CS. […] Although numerous abnormalities in the hemostatic system have been detected in patients with CS, the underlying mechanisms of the prothrombotic state are not fully elucidated. High levels of factor VIII and von Willebrand factor, with evidence of enhanced thrombin generation and decreased fibrinolytic activity, have been documented in several studies. […] Thrombosis is usually a multicausal disease, and all three components of the so-called Virchow triad, namely 1) vascular abnormalities and endothelial dysfunction, 2) hypercoagulability and 3) stasis, may play a variable role in the pathogenesis of the prothrombotic state in CS patients. Larger studies are needed to establish strategies for prevention of cardiovascular complications in patients with Cushings syndrome.

• #1 Glucocorticoid Therapy and Cushing Syndrome: Background, Pathophysiology, Endogenous Cushing syndrome

  https://emedicine.medscape.com/article/921086-overview

  The glucocorticoid receptor is an intracellular protein that, in its ligand-bound form, acts as a nuclear transcription factor to regulate the expression of a diverse array of genes in many areas of the body. […] Factors that influence the spectrum of adverse effects observed in hypercortisolemic individuals include duration of treatment, potency of the steroid, dose and route of administration, and the site and rate of metabolism and clearance. […] Since the late 1940s, when glucocorticoids first came into use for their anti-inflammatory and immunomodulatory effects, much work has been conducted by science and industry to maximize their beneficial effects while minimizing their adverse effects. […] Alterations of the basic steroid nucleus and its side groups give rise to the pharmacologic differences between these chemicals. Such changes may affect the bioavailability of these steroid compounds, including their GI absorption; parenteral distribution; plasma half-life; their metabolism in the liver, fat, or target tissues; and their ability to interact with the GR and MR and modulate the transcription of glucocorticoid-responsive genes. […] Ectopic expression of receptors on cortisol-producing cells, resulting in hypercortisolemia shown in some cases.

• #1 Advances in Molecular Pathophysiology and Targeted Therapy for Cushing’s Disease

  https://www.mdpi.com/2072-6694/15/2/496

  The proposed model for the nuclear translocation pathways, including complex formation of GR, has been disputed. HSP90 was traditionally thought to act as one of the anchoring proteins that retain GR in the cytoplasm. After glucocorticoid binding, the activated GR dissociates from the HSP90 complex and translocates to the nucleus. However, it has also been reported that GR remains in the HSP90 complex and is transported into the nucleus after glucocorticoid binding-induced substitution of FK506-binding immunophilin 5 (FKBP5) for FKBP4, and recruitment of the transport protein dynein, resulting in GR converting to the DNA-binding form in the nucleus. […] The mutations hyperactivate ubiquitin-specific protease 8 (USP8), resulting in the inhibition of epidermal growth factor receptor (EGFR) degradation. Thus, increased EGFR stability contributes to the maintenance of EGFR signaling in Cushing’s disease. The Janus kinase/signal transducer and activator of transcription (Jak/STAT) is located downstream of EGFR signaling and is essential for EGFR-driven migration and invasion. Phosphorylated STAT3 is required for Pomc transcription.

• #1 cushing | Calgary Guide

  https://calgaryguide.ucalgary.ca/?s=cushing

  Cushing’s syndrome (symptoms and signs caused by prolonged cortisol exposure) Muscle weakness, hyperglycemia, severe hypokalemia […] Excess cortisol in the renal tubule saturates the enzyme 11- HSD2, which converts cortisol to cortisone Capacity of body to convert cortisol to cortisone is exceeded Excess cortisol can mimic aldosterone and bind to mineralocorticoid receptors (cortisone cant bind to these receptors) Aldosterone effect Na+ reabsorption from the cortical collecting duct into blood vessels […] Both primary Cushings (e.g. adenomas that extend into zona reticularis of the adrenal cortex) and central/secondary Cushings (e.g. ACTH stimulation of zona reticularis) are associated with adrenal androgen secretion […] Serum cortisol leads to Intestinal Ca2+ absorption and renal Ca2+ reabsorption Serum Ca2+ PTH secretion

• #1 Genetic Changes Found in Cushing’s Disease, Adrenal Tumors and Adrenal Hyperplasia – CSRF – Cushing’s Support & Research Foundation

  https://csrf.net/doctors-articles/molecular-mechanism-of-cushings/genetic-changes-found-in-cushings-disease-adrenal-tumors-and-adrenal-hyperplasia/

  Cushings patients often ask their physicians what caused their rare disease; they want to know if it has anything to do with their DNA and whether it can be inherited. Changes in the building blocks of genes (i.e., mutations) do indeed play a role in the development of tumors that increase adrenocorticotropic hormone (ACTH) or cortisol secretion. […] Most ACTH-secreting pituitary tumors (Cushings disease) are not hereditary and result from a mutation to a single ACTH-secreting cell sometime after birth. […] The cause of Cushings disease (an ACTH-secreting pituitary tumor) is overgrowth of one ACTH-producing cell in the pituitary, which multiplies abnormally to become a benign tumor that produces too much ACTH; this causes a continuous signal to the adrenal glands to secrete cortisol. […] The genes responsible for the abnormal growth of a pituitary ACTH-secreting cell have not been identified.

• #1 Cushing’s disease: towards precision medicine | Cell Research

  https://www.nature.com/articles/cr201553

  The pathogenesis of Cushing’s disease is poorly understood; two recent reports identifying somatic mutations in USP8 in pituitary corticotroph tumors provide exciting advances in this field. […] The causes of CD are largely unknown. While generally not familial, CD has been reported in association with multiple endocrine neoplasia type 1 due to mutations in MEN1, familial isolated pituitary adenoma (AIP), McCune-Albright syndrome (GNAS), Carney complex (PRKAR1A), and MEN4 (CDKN1B). […] In this landscape of a dearth of insight into the pathogenesis of CD, recent reports from two independent groups demonstrating the association of somatic mutations in USP8 with corticotroph tumors, identified by whole-exome sequencing of tumor tissue DNA, represent an exciting leap forward in our understanding of the pathogenesis of this disorder and may contribute to important advances in targeted therapy.

• #1 Genetic Changes Found in Cushing’s Disease, Adrenal Tumors and Adrenal Hyperplasia – CSRF – Cushing’s Support & Research Foundation

  https://csrf.net/doctors-articles/molecular-mechanism-of-cushings/genetic-changes-found-in-cushings-disease-adrenal-tumors-and-adrenal-hyperplasia/

  New genetic methods have been used to find mutations in genes that are particularly important in ACTH-producing cells, but studies have not yet identified one gene that is common to most pituitary tumors. […] Several different mutations have been identified in adrenal adenomas; however, they seemed to be important in only a very few cases. […] This mutation was found in 37% of adrenal adenomas from patients with obvious Cushings syndrome. […] This specific mutation was not found in cells outside of the tumor, indicating that this mutation occurred after birth. […] Some cases of bilateral adrenal hyperplasia have been reported to occur in families, indicating that inherited genetic defects are involved. […] PPNAD and Carney complex have been extensively studied and inheritable mutations of important genes PRKAR1A, PDE11A or PDE8B, which regulate signals to produce cortisol, have been identified in a large number of affected patients.

• #1 Treatment of Cushing’s disease: a mechanistic update in: Journal of Endocrinology Volume 223 Issue 2 (2014)

  https://joe.bioscientifica.com/view/journals/joe/223/2/R19.xml

  Cushing’s disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamuspituitaryadrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. […] A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future. […] Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. […] The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment.

• #1 Cushing’s Disease and Mechanism of Action of Drugs – My Endo Consult

  https://myendoconsult.com/learn/cushings-disease-and-mechanism-of-action-of-drugs/

  The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through a complex system of stimulatory and inhibitory mechanisms. […] Cortisol, in turn, provides negative feedback by suppressing the release of CRH and AVP in the hypothalamus, as well as ACTH in the pituitary gland. […] Both normal and abnormal corticotroph cells in the pituitary gland have two types of somatostatin receptors: SSR2 and SSR5. […] Pasireotide is a medication that mimics the effects of somatostatin and targets four out of the five somatostatin receptor types: SSR1, SSR2, SSR3, and SSR5. […] Retinoic acid (RA) lowers cortisol levels in individuals with Cushings disease through multiple mechanisms. […] These combined actions make RA a promising therapeutic option for managing Cushings disease.

• #1 Cushing’s Disease and Mechanism of Action of Drugs – My Endo Consult

  https://myendoconsult.com/learn/cushings-disease-and-mechanism-of-action-of-drugs/

  The mechanisms of action for metyrapone, mitotane, ketoconazole, and the newly approved steroidogenesis inhibitor, osilodrostat, are as follows: […] These drugs target various stages of cortisol production, offering therapeutic options for conditions like Cushings syndrome that involve excess cortisol levels.

• #1 Cushing disease medications (Mechanism of Action) – My Endo Consult

  https://myendoconsult.com/learn/cushing-disease-medications-mechanism-of-action/

  Mifepristone (RU-486) is a synthetic steroid with anti-progestational and anti-glucocorticoid activity. It is a competitive inhibitor of progesterone and cortisol at the glucocorticoid receptor, and thus prevents the maturation of the corpus luteum, suppresses ovulation, and antagonizes the action of endogenous cortisol.

• #1

  https://link.springer.com/article/10.1007/s40618-021-01661-x

  Cushings Syndrome (CS), or chronic endogenous hypercortisolism, is a rare and serious disease due to corticotroph pituitary (Cushings disease, CD) and extra-pituitary (ectopic CS) tumours overproducing ACTH, or cortisol-secreting adrenal tumours or lesions (adrenal CS). […] Corticotroph pituitary and extra-pituitary tumours, as well as adrenal tumours and lesions responsible for CS express dopamine receptors (DRs), which have been found to mediate inhibition of hormone secretion and/or cell proliferation in experimental setting, suggesting that dopaminergic system, particularly DRs, might represent a target for the treatment of CS. […] The expression of DRs in the hypothalamus-pituitary-adrenal (HPA) axis and in the diffuse neuroendocrine system in physiological or pathological conditions suggests a potential role of the dopaminergic system in the regulation of HPA axis and diffuse neuroendocrine system and a potential role of the dopaminergic drugs in the management of CS.

• #1 Atumelnant (oral ACTH Antagonist) Cushing’s Syndrome, CAH

  https://crinetics.com/pipeline/atumelnant-cushings-syndrome-cah/

  ACTH acts through the melanocortin type 2 receptor (MC2R) that is primarily expressed in the adrenal gland. This is the first reported oral, selective ACTH antagonist discovered by our team in development for the treatment of ACTH-dependent Cushing’s syndrome and other diseases of excess ACTH, such as congenital adrenal hyperplasia. […] ACTH-dependent Cushing’s syndrome results from a pituitary tumor that secretes excess ACTH, which in turn causes the downstream synthesis and over-secretion of cortisol by the adrenal glands. Cortisol is the body’s main stress hormone and excess amounts can cause significant increases in mortality and morbidity. […] CAH encompasses a set of disorders caused by genetic mutations that result in impaired cortisol synthesis. This lack of cortisol leads to a breakdown of feedback mechanisms and results in persistently high levels of ACTH, which in turn causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects, from improper gonadal development to life-threatening dysregulation of mineralocorticoids.

• #1 New Trends in Treating Cushing’s Disease – touchENDOCRINOLOGY

  https://touchendocrinology.com/pituitary/journal-articles/new-trends-in-treating-cushings-disease/

  Corticotroph adenomas overexpress HSP90, resulting in increased binding to the glucocorticoid receptor, thereby inhibiting its translocation and subsequent DNA binding. […] Therefore, HSP90 plays a significant role in controlling POMC expression. […] Overexpression of HSP90 contributes to the partial resistance of tumour cells to glucocorticoids. […] For that reason, an HSP90 inhibitor may dissociate the glucocorticoid receptor from HSP90, increasing the negative feedback of glucocorticoids at the pituitary level and modulating ACTH secretion. […] Epigenetics is an emerging field of cancer research and drug investigation. […] That being said, histone deacetylase (HDAC) inhibitors are compounds with promising antineoplastic properties. […] Generally, in cancer, acetylation of chromatin is disrupted, and HDAC inhibition might lead to increased expression of tumour suppressor genes and reduced expression of oncogenes. […] The management of recurrent or persistent corticotroph adenoma requires an individualized approach by an experienced multidisciplinary team. […] Research on the pathogenesis of corticotroph adenomas has opened new avenues for discovering and developing new treatment options.

• #1 Endogenous Cushing’s Syndrome — Sparrow Pharmaceuticals

  https://sparrowpharma.com/endogenous-cushings-syndrome

  Endogenous Cushings syndrome (Cushings), also referred to as hypercortisolism, is the result of exposure to excess cortisol over an extended period of time. […] Cushings is caused by a secreting tumor often found on the pituitary or adrenal gland. The tumor, usually non-cancerous, causes an overproduction of cortisol. […] Our proprietary HSD-1 inhibitor, clofutriben, utilizes a novel mechanism of action to target a source of cortisol causing health problems, and has the potential to safely and effectively alleviate its associated symptoms. Additionally, HSD-1 inhibition may not share the undesirable effects of completely blocking the glucocorticoid receptor, lowering ACTH, or inhibiting multiple steroidogenic enzymes, as currently approved therapies do.

• #2 Cushing syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310

  Cushing syndrome happens when the body has too much of the hormone cortisol for a long time. This can result from the body making too much cortisol, or from taking medicines called glucocorticoids, which affect the body the same way as cortisol. […] Cushing syndrome is caused by having too much cortisol in the body. Cortisol is a hormone that is made in the adrenal glands. […] A hormone made in the pituitary gland controls how much cortisol the body makes. This is called adrenocorticotropic hormone (ACTH). Some tumors make ACTH, which creates more cortisol and can cause Cushing syndrome. Problems with the adrenal glands also can affect cortisol and cause Cushing syndrome. […] When Cushing syndrome happens this way, it may be caused by: ACTH-producing pituitary adenoma. Pituitary adenomas are tumors that grow in the pituitary gland.

• #2 Cushing’s Disease and Mechanism of Action of Drugs – My Endo Consult

  https://myendoconsult.com/learn/cushings-disease-and-mechanism-of-action-of-drugs/

  The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through a complex system of stimulatory and inhibitory mechanisms. […] Cortisol, in turn, provides negative feedback by suppressing the release of CRH and AVP in the hypothalamus, as well as ACTH in the pituitary gland. […] Both normal and abnormal corticotroph cells in the pituitary gland have two types of somatostatin receptors: SSR2 and SSR5. […] Pasireotide is a medication that mimics the effects of somatostatin and targets four out of the five somatostatin receptor types: SSR1, SSR2, SSR3, and SSR5. […] Retinoic acid (RA) lowers cortisol levels in individuals with Cushings disease through multiple mechanisms. […] These combined actions make RA a promising therapeutic option for managing Cushings disease.

• #2 Cushing Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448184/

  Cushing disease is an endocrine disorder characterized by excessive adrenocorticotropic hormone (ACTH) production by the anterior pituitary, which leads to the release of an excess of cortisol from the adrenal glands. […] A pituitary adenoma often causes this, or it results from excess production of corticotropin-releasing hormone (CRH) from the hypothalamus. […] In Cushing disease, the frequency of ACTH production remains the same, but the normal circadian rhythm is lost. The increased plasma ACTH causes bilateral adrenal hyperplasia and a consequent increase in the production of cortisol. Therefore, the normal circadian rhythm of cortisol is also lost. […] Cortisol functions primarily as a glucocorticoid; however, in high concentrations, cortisol can also exhibit mineralocorticoid activity, leading to hypertension and hypokalemia through the renin-angiotensin-aldosterone system.

• #2 Cushing’s syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Cushing%27s_syndrome

  Cushing’s syndrome is caused by either excessive cortisol-like medication, such as prednisone, or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands. […] Cushing’s disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma (secondary hypercortisolism/hypercorticism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism). This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. […] When Cushing’s syndrome is due to extra ACTH it is known as ectopic Cushing syndrome. […] The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on CRH in the hypothalamus, which decreases the amount of ACTH released from the anterior pituitary gland.

• #2 Advances in Molecular Pathophysiology and Targeted Therapy for Cushing’s Disease

  https://www.mdpi.com/2072-6694/15/2/496

  Cushing’s disease is caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from corticotroph pituitary neuroendocrine tumors. As a result, excess cortisol production leads to the overt manifestation of the clinical features of Cushing’s syndrome. Severe complications have been reported in patients with Cushing’s disease, including hypertension, menstrual disorders, hyperglycemia, osteoporosis, atherosclerosis, infections, and mental disorders. […] In Cushing’s disease, the dysregulation of ACTH synthesis and secretion is caused by corticotroph tumors. Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been reported in corticotroph tumors and play an important role in ACTH production. The mutation increases the enzyme’s activity, which results in excessive deubiquitination of epidermal growth factor receptor (EGFR) tyrosine kinase, disturbing its degradation.

• #2 New Trends in Treating Cushing’s Disease – touchENDOCRINOLOGY

  https://touchendocrinology.com/pituitary/journal-articles/new-trends-in-treating-cushings-disease/

  This gene codes for a protein with deubiquitinase activity, which rescues proteins such as EGFR from lysosomal degradation. […] Mutated USP8 exerts higher deubiquitinase activity, probably explaining the aberrant EGFR signalling in corticotrophs. […] It is estimated that 16.5% of USP8 wild-type corticotroph adenomas carry BRAF (B-raf proto-oncogene, serine/threonine kinase) mutations encoding p.V600E, resulting in increased MAPK (mitogen-activated protein kinase) activity and subsequent POMC expression. […] A BRAF-kinase inhibitor, vemurafenib, was reasonably evaluated, and it was discovered to suppress ACTH secretion from primary cultures of human corticotroph adenomas harbouring BRAF V600E. […] Heat shock protein 90 (HSP90) is a chaperone protein that induces conformational changes in the glucocorticoid receptor, among others, and affects its transcriptional activity.

• #2 Cushing syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310

  Rarely, a tumor that makes too much ACTH grows in an organ that usually doesn’t make ACTH. This is called ectopic ACTH production. It causes the body to make too much cortisol. […] Problems with the adrenal glands can cause them to make too much cortisol. The most common is a tumor in the outer part of the adrenal gland called an adrenal adenoma. […] Rarely, people inherit a tendency to get tumors on one or more of their endocrine glands, which are glands that make hormones. If these tumors make ACTH or cortisol, Cushing syndrome can happen.

• #2 Endogenous Cushing Syndrome: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2233083-overview

  Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. Exogenous use of glucocorticoids should always be considered and excluded in the etiology of Cushing syndrome. This article focuses on endogenous Cushing syndrome. Endogenous glucocorticoid overproduction, or hypercortisolism, can be dependent on or independent of adrenocorticotropic hormone (ACTH). […] Endogenous glucocorticoid overproduction, or hypercortisolism, that is independent of ACTH is usually due to a primary adrenocortical neoplasm (most commonly an adenoma and rarely a carcinoma). Bilateral micronodular hyperplasia (primary pigmented nodular adrenocortical disease) and macronodular hyperplasia are rare causes of Cushing syndrome. […] ACTH-independent Cushing syndrome is most often due to a primary cortisol-producing adrenal adenoma or carcinoma, assuming exogenous glucocorticoid use has been excluded. A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor. An ACTH level greater than 20 pg/mL (4.4 pmol/L) is consistent with ACTH-dependent Cushing syndrome. An ACTH level between 5 and 20 pg/mL is equivocal.

• #2 Glucocorticoid Therapy and Cushing Syndrome: Background, Pathophysiology, Endogenous Cushing syndrome

  https://emedicine.medscape.com/article/921086-overview

  Cushing syndrome (CS) takes its name from Harvey Cushing, who, in 1912, was one of the first physicians to report a patient affected with excessive glucocorticoid. More than 99% of cases of Cushing syndrome are due to administration of excessive amounts of glucocorticoid. […] Although distinguishing endogenous from exogenous Cushing syndrome is usually straightforward, the investigation and differentiation of Cushing syndrome from other causes of hypercortisolism require a sound understanding of the physiology of the hypothalamic-pituitary-adrenal (HPA) axis. […] Glucocorticoid synthesis and release is strictly regulated by the pituitary and hypothalamus by negative feedback and, to a lesser extent, by catecholamines from the adrenal medulla and neural inputs from the autonomic system. In addition to the glucocorticoid effects that cortisol has because of binding to the glucocorticoid receptor (GR), cortisol can also bind to and activate the mineralocorticoid receptor (MR).

• #2 Cushing’s Syndrome – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/cushings-syndrome

  Cushing’s syndrome results from excessive glucocorticoid excretion, which has multi-systemic effects. […] Glucocorticoids induce hyperglycemia via gluconeogenesis and insulin resistance, potentially leading to type 2 diabetes. […] Glucocorticoids also contribute to hypertension by increasing sodium reabsorption and catecholamine sensitivity, leading to vasoconstriction. […] Additionally, glucocorticoids cause skin changes like purple striae, muscle weakness, and osteoporosis by altering collagen, muscle, and calcium metabolism, respectively. […] Cushing’s disease is a form of Cushing’s syndrome caused by an ACTH-secreting pituitary adenoma, leading to elevated ACTH and cortisol levels as well as bilateral adrenal hyperplasia. […] In contrast, a cortisol-secreting adrenal tumor, either an adenoma or carcinoma, results in ACTH-independent Cushing’s syndrome.

• #2 Cushing’s syndrome and hypertension | ECE2015 | 17th European Congress of Endocrinology | Endocrine Abstracts

  https://www.endocrine-abstracts.org/ea/0037/ea0037ep29

  Patients with Cushings syndrome (CS) are prone to hypertension as cortisol stimulates renal reabsorption of sodium and enhances vascular sensitivity to catecholamine and angiotensin II. […] Hypertension is frequent in CS, its association with diabetes, dyslipidaemia and a pro-coagulant state also frequent in CS explain the high frequency of cardiovascular events in hypercortisolism states.

• #2 Cushing’s syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cushing%27s_syndrome_pathophysiology

  Both the hypothalamus and the pituitary gland are part of the brain. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing’s syndrome refers to excess cortisol of any etiology. One of the causes of Cushing’s syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing’s disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels. Cortisol can also exhibit mineralocorticoid activity in high concentrations, worsening hypertension and leading to hypokalemia (common in ectopic ACTH secretion).

• #2 Amenorrhea as a presentation of Cushing’s syndrome in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2024 Issue 3 (2024)

  https://edm.bioscientifica.com/view/journals/edm/2024/3/EDM23-0152.xml

  Menstrual cycle abnormalities are common in premenopausal females with Cushings syndrome, although the underlying mechanism is poorly understood. […] In Cushing’s syndrome, female patients can have menstrual abnormalities due to the high cortisol levels, which can affect gonadotrophin levels. […] Menstrual cycle abnormalities are common in premenopausal females with Cushings syndrome, although the underlying mechanism is poorly understood. […] Lado-Abeal et al. observed that menstrual irregularities in Cushing’s syndrome are due to hypogonadotropic hypogonadism, as opposed to PCOS patients. This finding is supported by the fact that these patients’ LH and FSH levels were inappropriately low for the estrogen levels in their blood. […] It has led to the conclusion that menstrual abnormalities in patients with Cushing’s syndrome are likely due to abnormal hypothalamic GnRH secretion caused by long-standing high cortisol levels, which block the secretion of GnRH from the hypothalamus and the action of LH and FSH on the ovaries.

• #2 Cushing’s disease: towards precision medicine | Cell Research

  https://www.nature.com/articles/cr201553

  The pathogenesis of Cushing’s disease is poorly understood; two recent reports identifying somatic mutations in USP8 in pituitary corticotroph tumors provide exciting advances in this field. […] The causes of CD are largely unknown. While generally not familial, CD has been reported in association with multiple endocrine neoplasia type 1 due to mutations in MEN1, familial isolated pituitary adenoma (AIP), McCune-Albright syndrome (GNAS), Carney complex (PRKAR1A), and MEN4 (CDKN1B). […] In this landscape of a dearth of insight into the pathogenesis of CD, recent reports from two independent groups demonstrating the association of somatic mutations in USP8 with corticotroph tumors, identified by whole-exome sequencing of tumor tissue DNA, represent an exciting leap forward in our understanding of the pathogenesis of this disorder and may contribute to important advances in targeted therapy.

• #2 Genetic Changes Found in Cushing’s Disease, Adrenal Tumors and Adrenal Hyperplasia – CSRF – Cushing’s Support & Research Foundation

  https://csrf.net/doctors-articles/molecular-mechanism-of-cushings/genetic-changes-found-in-cushings-disease-adrenal-tumors-and-adrenal-hyperplasia/

  Research over the past 20 years has shown that some patients with bilateral macronodular adrenal hyperplasia show increased cortisol production in response to hormones other than ACTH, such as gastric inhibitory polypeptide (GIP), vasopressin, adrenalin, serotonin, and human chorionic gonadoptropin (hCG), but the genetic basis of the hyperplasia remained a mystery. […] A recent series of studies looked at bilateral macronodular adrenal hyperplasia tissue and found a mutation in a gene called ARMC5. […] The hyperplasia cells that were not in the nodules contained only the inheritable germline mutation. […] These studies point out the importance of examining family members of patients with bilateral macronodular adrenal hyperplasia to detect possible silent carriers of the same disease and those with subclinical Cushings syndrome. […] In summary, the genetic basis for pituitary tumors responsible for Cushings disease is still unknown, but new target proteins that can regulate their growth are under study.

• #2 Treatment of Cushing’s disease: a mechanistic update in: Journal of Endocrinology Volume 223 Issue 2 (2014)

  https://joe.bioscientifica.com/view/journals/joe/223/2/R19.xml

  Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. […] Pharmacological agents can be classified as adrenal steroidogenesis blockers, centrally acting drugs, and GR antagonists. […] Recent research has evaluated chimeric compounds that work synergistically through membrane interaction or dimerization of both somatostatin receptors (SSTRs) and dopamine D2 receptors in corticotrope cells. […] The pharmacotherapies for ACTH-secreting pituitary corticotrope adenomas are categorized by the site of action into three groups: i) centrally acting agents or neuromodulators, which inhibit ACTH release from pituitary adenomas, ii) adrenal steroidogenic inhibitors, which block one or several steps in cortisol biosynthesis and iii) the glucocorticoid receptor-blocking agent mifepristone. […] A review of the mechanisms of current and future medical treatment modalities for CD is provided.

• #2 Cushing disease medications (Mechanism of Action) – My Endo Consult

  https://myendoconsult.com/learn/cushing-disease-medications-mechanism-of-action/

  Somatostatin analogs are drugs that mimic the action of somatostatin, a hormone that inhibits the release of other hormones, including cortisol. The most commonly used somatostatin analog is pasireotide (Signifor), which is effective in lowering cortisol levels and improving symptoms. […] Retinoic acid (RA) is a medical treatment for Cushings syndrome. RA works by inhibiting the production of COUP-TF1, a protein that is essential for cortisol synthesis. As a result, RA can help to reduce the levels of cortisol in the body and improve the symptoms of Cushings syndrome. While RA is not a cure for Cushings syndrome, it can help to manage the condition and improve the quality of life for patients. […] Steroidogenesis inhibitors are a class of drugs that are used to treat Cushings syndrome by reducing the production of cortisol. The most common agents in this class are ketoconazole, metyrapone, and mitotane. These drugs work by inhibiting the enzymes involved in cortisol synthesis in the adrenal gland. While they are effective at reducing cortisol levels, they can also cause significant side effects, such as gastrointestinal distress, adrenal insufficiency, and hepatotoxicity.

• #2 Cabergoline for Cushing’s disease: A case report | Endocrinología y Nutrición

  https://www.elsevier.es/es-revista-endocrinologia-nutricion-12-articulo-cabergoline-for-cushing39s-disease-a-S1575092215001783

  Cushing’s syndrome results from a prolonged exposure to excessive concentrations of free circulating glucocorticoids. ACTH dependent Cushing’s syndrome or Cushing’s disease (CD) represents approximately 80-85% of the total cases, and around 80% of them correspond to ACTH secreting pituitary adenomas. […] In the mechanistic analysis the authors demonstrated the presence of D2 dopamine receptors in the primary tumor and its expression was similar to what is found in prolactinomas. […] Although the beneficial effect of cabergoline in the pituitary ACTH-secreting adenomas could be evident (in view of this and others results), the clinical experience is limited although not entirely new. […] In conclusion, cabergoline may be a good therapeutic alternative in the medical treatment of CD, given its modulatory effect on the release of ACTH and its possible impact on reducing tumor size.

• #2 Atumelnant (oral ACTH Antagonist) Cushing’s Syndrome, CAH

  https://crinetics.com/pipeline/atumelnant-cushings-syndrome-cah/

  We have ongoing efforts to advance the first nonpeptide product candidate to antagonize the peptide adrenocorticotrophic hormone (ACTH) designed for the treatment of ACTH-dependent Cushing’s syndrome, CAH, and other diseases of ACTH excess. […] CRN04894 an oral, nonpeptide ACTH receptor antagonist reverses ACTH-stimulated glucocorticoid secretion in rodents and humans. […] Inhibition of Basal and ACTH-Stimulated Cortisol Secretion in Humans Using an Oral, Nonpeptide ACTH Antagonist (CRN04894). […] Discovery and Identification of Late Stage, Selective, Nonpeptide, ACTH Antagonists for the Treatment of Cushing’s Disease, Ectopic ACTH Secreting Tumors, and Congenital Adrenal Hyperplasia. […] Nonpeptide, Orally Bioavailable ACTH Antagonists: Suppression of ACTH-induced Corticosterone Secretion and Adrenal Hypertrophy in Rats.

• #3 New Trends in Treating Cushing’s Disease – touchENDOCRINOLOGY

  https://touchendocrinology.com/pituitary/journal-articles/new-trends-in-treating-cushings-disease/

  Rates of recurrence and/or persistence of Cushings disease after surgical treatment are high. […] Recently, advances in molecular insights and a better understanding of pathophysiology have enabled the development of potential therapeutic targets that could control adrenocorticotropic hormone (ACTH) and cortisol secretion or even reduce tumour cell proliferation. […] At the pituitary level, pasireotide is an approved somatostatin receptor ligand, and compounds targeting cell cycle regulation, cell signalling and epigenetics are now under investigation. […] More than half of pituitary tumours, including corticotroph adenomas, express epidermal growth factor receptor (EGFR), which plays a key role in POMC expression. […] Interestingly, 36-62% of corticotroph adenomas show gain-of-function mutations in the gene encoding for USP8.

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