Materiały źródłowe

• #1 Acromegaly pathogenesis and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2769196/

  Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly a disorder of disproportionate skeletal, tissue, and organ growth. […] Disease pathogenesis involves growth hormone (GH) hypersecretion by tumorous pituitary somatotroph cells, and the diagnosis is invariably preceded by about 10 years of active but unrecognized disease. […] Chronic exposure to GH and IGF1 hypersecretion leads to soft tissue swelling of tongue, heart, kidney, colon, and vocal cords and periarticular and cartilaginous thickening, resulting ultimately in painful large-joint osteoarthritis. […] Mechanistic studies of human pituitary tumors have been constrained due to inaccessibility of the gland for biopsy, lack of functional cell lines, and unique differentiated tumor subtype behavior. In most cases of acromegaly, GH hypersecretion is derived from somatotroph cell tumors.

• #2

  https://www.jci.org/articles/view/39375

  Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly a disorder of disproportionate skeletal, tissue, and organ growth. […] Disease pathogenesis involves growth hormone (GH) hypersecretion by tumorous pituitary somatotroph cells, and the diagnosis is invariably preceded by about 10 years of active but unrecognized disease. […] Chronic exposure to GH and IGF1 hypersecretion leads to soft tissue swelling of tongue, heart, kidney, colon, and vocal cords and periarticular and cartilaginous thickening, resulting ultimately in painful large-joint osteoarthritis. […] Mechanistic studies of human pituitary tumors have been constrained due to inaccessibility of the gland for biopsy, lack of functional cell lines, and unique differentiated tumor subtype behavior. In most cases of acromegaly, GH hypersecretion is derived from somatotroph cell tumors.

• #3 Acromegaly pathogenesis and treatment | Catalogue | State Library of New South Wales

  https://search.sl.nsw.gov.au/primo-explore/fulldisplay?docid=TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2769196&context=PC&vid=SLNSW

  Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly – a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.

• #4 Acromegaly – Wikipedia

  https://en.wikipedia.org/wiki/Acromegaly

  Acromegaly is a disorder that results in excess growth of certain parts of the human body. It is caused by excess growth hormone (GH) after the growth plates have closed. […] About 98% of cases of acromegaly are due to the overproduction of growth hormone by a benign tumor of the pituitary gland called an adenoma. These tumors produce excessive growth hormone and compress surrounding brain tissues as they grow larger. […] Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell that leads to increased cell division and tumor formation. […] Pituitary adenomas and diffuse somatomammotroph hyperplasia may result from somatic mutations activating GNAS, which may be acquired or associated with McCune–Albright syndrome.

• #5 Acromegaly | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-17

  Acromegaly is characterized by an acquired progressive somatic disfigurement, mainly involving the face and extremities, but also many other organs, that is associated with systemic manifestations. The disease is related to the excessive production of growth hormone (GH). This GH hypersecretion originates from a monoclonal benign pituitary tumor (adenoma) in more than 90% of cases. […] In the majority of cases, acromegaly is related to a pituitary adenoma, either purely GH-secreting (60%) or mixed. In very rare cases, acromegaly is due to ectopic secretion of growth-hormone-releasing hormone (GHRH) responsible for pituitary hyperplasia. […] The pituitary/hypothalamic origin of these adenomas is controversial. Some lines of evidence point to a hypothalamic origin. In this case, the main actor would be growth-hormone-releasing hormone (GHRH), which can cause not only hyperplasia of somatotrope cells but also, as demonstrated in some animal models, actual adenomas. In contrast, the monoclonal nature of the tumors and the absence of relapse after total tumor resection points instead to a pituitary origin.

• #6 Acromegaly – Wikipedia

  https://en.wikipedia.org/wiki/Acromegaly

  In a few people, acromegaly is caused not by pituitary tumors, but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH (growth hormone-releasing hormone), the hormone that stimulates the pituitary to make GH.

• #7 Acromegaly – Hypothalamus and Pituitary Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.8.10.

  Causes such as growth hormone-releasing hormone (GHRH) excess from hypothalamic lesions or peripheral ectopic sources (neuroendocrine tumors [NETs]) are extremely rare. GH-secreting pituitary carcinomas and ectopic GH-releasing tumors are even more rare. Iatrogenic GH administration may also cause acromegaly.

• #8

  https://www.jci.org/articles/view/39375

  GH-secreting tumor formation ensues as a consequence of unrestrained somatotroph proliferation associated with intrinsic cell-cycle dysfunction as well as altered endocrine and or paracrine factors regulating GH synthesis, GH secretion, and somatotroph cell growth. […] Several lines of evidence support the role of the GHRH-cAMP signaling pathway in mediating somatotroph tumorigenesis. […] About 40% of patients with sporadic acromegaly harbor GNAS mutations with aa substitutions at Arg201 or Gln227, leading to constitutively elevated cAMP with no distinctive clinical phenotype. […] The cAMP pathway may be constitutively activated. […] Thus, accumulated pituitary DNA damage and senescence, hallmarks of GH-secreting adenomas, likely enable a benign phenotype.

• #9 Genetic and Epigenetic Pathogenesis of Acromegaly

  https://www.mdpi.com/2072-6694/14/16/3861

  The genetic abnormalities that cause somatotroph tumors can be broadly classified into germline and somatic mutations, but recent advances suggest that these abnormalities are not only gene mutations but also copy number variations and epigenetic abnormalities. Although 40% of somatotroph tumors are caused by somatic mutations in the Guanine nucleotide activating subunit (GNAS) gene and the additional portion can be explained by the handful of classified rare germline mutations, the cause of almost half of all somatotroph tumors remains unclarified. […] The most common cause of somatotroph tumors is somatic mutations in the GNAS gene, 20q13.3. These mutations result in amino acid substitutions at Arg201 and Gln227, resulting in the constitutive active mutation of the Gsα subunit. These lead to excessive cAMP and PKA signaling, resulting in autonomous secretion of GH.

• #10 Gigantism and Acromegaly: Background, Pathophysiology and Etiology, Epidemiology

  https://emedicine.medscape.com/article/925446-overview

  Activating mutations of the stimulatory Gsa protein have been found in the pituitary lesions in McCune-Albright syndrome and are believed to cause the other glandular adenomas observed. […] Somatic point mutations have been identified in the somatotrophs of less than 40% of sporadic GH-secreting pituitary adenomas. […] The resulting oncogene (gsp) is thought to induce tumorigenesis by persistently activating adenyl cyclase, with subsequent GH hypersecretion. […] Causes of secondary GH excess include increased secretion of GHRH due to an intracranial or ectopic source and dysregulation of the hypothalamic-pituitary-GH axis. […] Hypothalamic GHRH excess is postulated as a cause for gigantism, possibly secondary to an activating mutation in hypothalamic GHRH neurons.

• #11 Genetic and Epigenetic Pathogenesis of Acromegaly

  https://www.mdpi.com/2072-6694/14/16/3861

  A small proportion of somatotroph tumors are caused by germ cell mutations in various genes including MEN1, CDKN1B, PRKAR1A, GNAS, AIP, GPR101, SDHx, MAX, NF1, IGFS1 and TSC. In these cases, they are generally familial and observed in young patients. […] Familial onset and genetic tumor syndromes are found in approximately 5% of all pituitary tumors, and the causative gene has been identified in some cases. In general, pituitary adenomas caused by genetic mutations are characterized by a younger age of onset, accelerated tumor growth and invasion, and resistance to surgery and medical therapy, especially to first-generation somatostatin analogs, making them more clinically challenging. […] Advances in genome analysis methods have led to the identification of several additional novel causative genes to GNAS mutation over the last 20 years. These evaluations have also facilitated the evaluation of various pathological mechanisms in these tumors, revealing that copy number variations and epigenetic abnormalities are also critical components in somatotroph tumors development. However, the cause of the majority of cases with somatotroph tumors remains unelucidated, highlighting the need for additional breakthrough studies. Recent advances in therapeutic strategies have enabled “a targeted therapy” based on the underlying mechanisms and responsible molecules. Therefore, it is critical to clarify the remaining causes to develop tailor-made therapies.

• #12

  https://www.jci.org/articles/view/39375/

  Several lines of evidence support the role of the GHRH-cAMP signaling pathway in mediating somatotroph tumorigenesis. […] About 40% of patients with sporadic acromegaly harbor GNAS mutations with aa substitutions at Arg201 or Gln227, leading to constitutively elevated cAMP with no distinctive clinical phenotype. […] The cAMP pathway may be constitutively activated. […] Thus, accumulated pituitary DNA damage and senescence, hallmarks of GH-secreting adenomas, likely enable a benign phenotype.

• #13

  https://www.jci.org/articles/view/39375/

  Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly a disorder of disproportionate skeletal, tissue, and organ growth. […] Disease pathogenesis involves growth hormone (GH) hypersecretion by tumorous pituitary somatotroph cells, and the diagnosis is invariably preceded by about 10 years of active but unrecognized disease. […] Mechanistic studies of human pituitary tumors have been constrained due to inaccessibility of the gland for biopsy, lack of functional cell lines, and unique differentiated tumor subtype behavior. In most cases of acromegaly, GH hypersecretion is derived from somatotroph cell tumors. […] GH-secreting tumor formation ensues as a consequence of unrestrained somatotroph proliferation associated with intrinsic cell-cycle dysfunction as well as altered endocrine and or paracrine factors regulating GH synthesis, GH secretion, and somatotroph cell growth.

• #14

  https://pfocr.wikipathways.org/figures/PMC2769196__JCI39375.f4.html

  GH transcription and somatotroph proliferation are induced by cAMP acting through CREB. […] In somatotroph tumors, the cAMP pathway may be constitutively activated. […] Furthermore, HMGA2 and PTTG, overexpression, and CDK inhibitor loss have been shown to result in experimental pituitary tumorigenesis. […] Chromosomal instability, DNA damage, and senescence, hallmarks of GH-secreting adenomas, may act to constrain malignant transformation of somatotroph tumors.

• #15 Acromegaly pathogenesis and treatment – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19884662/

  Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly – a disorder of disproportionate skeletal, tissue, and organ growth. […] High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. […] Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder. […] GH synthesis and secretion are induced by hypothalamic GHRH and gut-derived ghrelin. […] Hypothalamic SRIF suppresses GH secretion mainly by high-affinity binding to SSTR2 and SSTR5 receptor subtypes expressed on somatotrophs. […] GH transcription and somatotroph proliferation are induced by cAMP acting through CREB. […] In somatotroph tumors, the cAMP pathway may be constitutively activated. […] Furthermore, HMGA2 and PTTG, overexpression, and CDK inhibitor loss have been shown to result in experimental pituitary tumorigenesis.

• #16 Pharmacological management of acromegaly: a current perspective in: Neurosurgical Focus Volume 29 Issue 4 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/29/4/2010.7.focus10168.xml

  Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factorI (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. […] The molecular genetics of tumorigenesis in acromegaly have been recently elucidated. Development and differentiation of somatotrophs, GH-producing cells in the anterior pituitary, are influenced by a gene named the Prophet of Pit-1 (PROP1), which is responsible for the embryological development of the cells of the Pit-1 (POU1F1) transcription factor lineage. The binding of Pit-1 to the GH promoter in the cell nucleus results in development and growth of somatotrophs and subsequent GH transcription. Growth hormone is a 191amino acid polypeptide synthesized and secreted in a pulsatile fashion by the anterior pituitary. Growth hormonereleasing hormone (GHRH) stimulates the synthesis and secretion of GH while somatostatin inhibits GH release, with both traveling in the portal vein and acting on somatotroph-specific transcription factors. The effects of GH are mediated by GH receptors found primarily in the liver and cartilage. Activation of the GH receptor results in phosphorylation of the receptor and Janus kinase 2 (JAK2) followed by the binding of signal transducer and activator of transcription (STAT) proteins to the complex. The STAT proteins then become phosphorylated, translocate into the cell nucleus, and initiate transcription of target proteins, such as IGF-I, which induces cell proliferation and inhibits apoptosis. The development of a GH-secreting tumor is the result of variables that affect the development and growth of somatotrophs and their hormone production. Approximately 40% of tumors appear to harbor a mutation in the -subunit of the Gs protein that results in constitutive activation of cyclic AMP. Overexpression of the pituitary tumortransforming gene (PTTG) protein and lost expression of the growth arrest and DNA damage-inducible (GADD) 45 protein, a proapoptotic factor, has been demonstrated in GH-secreting pituitary adenomas. Overproliferation of somatotrophs and the resultant excessive secretion of GH results in acromegaly.

• #17 Frontiers | Molecular targets in acromegaly

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1068061/full

  Several other non-oncogenic factors play important pathogenic roles, including stimulatory signals from central and peripheral hormones, and disruption of proteins and kinases that regulate the cell cycle. […] Cell surface receptors for somatostatin, GHRH, and dopamine play a less direct role in pathogenesis, but are important mediators of stimulatory and inhibitory signals, and their balance is required to maintain normal GH secretory physiology. […] Somatotroph adenomas are classified in two immunohistochemical subtypes – sparsely or densely granulated – with important clinical implications. […] The mechanism of AIP mutation and tumorigenesis likely involves alterations in PDE4 phosphodiesterases as well as defective cAMP signaling. […] The molecular profile of acromegaly affords an array of potential targets that may predict tumor aggressiveness or treatment response.

• #18 Acromegaly: Pathophysiological Considerations and Treatment Options Including the Evolving Role of Oral Somatostatin Analogs

  https://www.mdpi.com/1873-149X/30/3/29

  Acromegaly is a disorder of the anterior pituitary which results in the overproduction of growth hormone (GH). The hypothalamic peptide growth hormone-releasing hormone (GHRH) provides the primary stimulus for the production of GH, while somatostatin provides negative feedback, decreasing GH secretion. GHRH secretion is modulated by a variety of factors, including sleep, diet, stress, and exercise. Somatostatin secretion is stimulated by factors including increased IGF-1 levels and low blood glucose levels. Excess GH also provides negative feedback to decrease pituitary GH secretion when serum GH levels are elevated. Pituitary GH secretion stimulates the production and release of insulin-like growth factor 1, IGF-1, from the liver. This subsequent disorder of hypersecretion of these stimulatory growth hormones, acromegaly, manifests as a product of the synergistic effects of tissue overgrowth produced by GH and IGF-1. Acromegaly is commonly identified by these systemic clinical effects of GH excess, including metabolic and physical development dysfunction.

• #19 Acromegaly pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acromegaly_pathophysiology

  Acromegaly pathogenesis depends mainly on the excessive secretion of the growth hormone from the pituitary gland. Pituitary somatotroph cell adenoma leads to hyper-secretion of the growth hormone. […] Acromegaly is believed to be caused by growth hormone (GH) secreting pituitary adenomas either microadenomas or macroadenomas. The pituitary adenoma leads to hypersecretion of the growth hormone from the somatotroph cells. […] In pituitary adenomas, a mutation in the alpha subunit of the guanine nucleotide stimulatory protein is responsible for the excess growth hormone secretion. The mutation in the alpha subunit will lead to increase synthesis of cAMP which is responsible for the growth of certain cells. Increase synthesis of cAMP will result in the increase secretion of the growth hormone. Signal transduction and transcription (STAT) induce production of IGF-1 from liver, bone and pituitary gland. The IGF-1 is responsible for the acral features of acromegaly. IGF-1 causes the rapid increase in the hand and feet size, forehead protrusion, and jaw prominence. The high level of IGF-1 is responsible for the following pathologic processes: IGF-1 is responsible for the diabetes mellitus which is common in 20% of patients with acromegaly. IGF-1 interferes with insulin on its receptor which leads to insulin resistance and hyperglycemia. IGF-1 causes hypertrophy of the body organs like the heart (cardiomegaly) and tongue (macroglossia).

• #20

  https://journals.lww.com/neur/fulltext/2020/68050/acromegaly_and_diabetes___a_hand_in_glove.65.aspx

  Acromegaly has a multitude of systemic manifestations, and one of them having serious ramifications are diabetes. […] Although diabetes is a widely known complication of increased growth hormone (GH) levels, the mechanism of diabetes is complex and intriguing in these patients. Under physiologic conditions in a normal person, GH is important for the growth of lean body mass, adipose tissue, and glycogen reserves and these actions are due to the positive effect of GH on hybrid insulin/IGF-1 (Insulin-like growth factor) receptors in adipose tissue, muscles, and hepatocytes, which ensures its insulin-like action. […] In acromegaly, there is a phenomenon of insulin resistance, which leads to decreased uptake of glucose and glycolysis in adipose tissue and increased gluconeogenesis in hepatocytes with resultant hyperglycemia and diabetes.

• #21 Acromegaly: a challenging condition to diagnose | IJGM

  https://www.dovepress.com/acromegaly-a-challenging-condition-to-diagnose-peer-reviewed-fulltext-article-IJGM

  The high level of IGF-1 in acromegaly is related to an increased risk of some cancers, particularly colon cancer and thyroid cancer. […] An increased incidence of micronucleus (MN) and oxidative DNA damage in lymphocytes of patients with acromegaly was found by Hamurcu et al. […] There is a direct correlation between the mortality rate and excess GH and IGF-1 secretion. […] Normalization of GH and IGF-1 has been found to reduce the mortality rate and disease-related morbidity. […] Improved understanding of the disease mechanism has led to the development of successful treatment modalities of acromegaly.

• #22 The effect of acromegaly on thyroid disease

  https://www.jstage.jst.go.jp/article/endocrj/70/11/70_EJ23-0356/_html/-char/en

  The single deiodination of T4 to T3 (activation pathway) is catalyzed by type 1 deiodinases (DIO1) and type 2 deiodinases (DIO2). […] An increase in the conversion of extrathyroidal T4 to T3 is mediated by GH. […] TSHR and IGF-1R co-localize and co-immunoprecipitate in orbital fibroblasts, orbital adipocytes, and primary human thyroid epithelial cells, forming a functional complex. […] Goiter is a common disease in patients with acromegaly. […] Goiter occurrence in patients with acromegaly is correlated to GH/IGF-1 levels. […] The occurrence of thyroid nodules in patients with acromegaly is associated with the disease course. […] Acromegaly treatment can improve thyroid nodules. […] Multiple studies have shown that compared with the general population, patients with acromegaly are at an increased risk of developing tumors, the most common of which is thyroid cancer, mainly papillary carcinoma, which may be related to the deleterious effects of high GH/IGF-1 levels in acromegaly.

• #23 Colorectal Neoplasm in Acromegaly: Epidemiology and Underlying Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/71367

  Furthermore, phosphorylated STAT5 in colon adenocarcinomas is associated with a poor prognosis. […] The phosphorylation of STAT5 is suppressed by suppressor of cytokine signaling-2 (SOCS2) in the GH signaling pathway. […] These data suggest the significance of excessive GH signaling in the development of epithelium-adenoma-carcinoma, independent of IGF-I signaling. […] Enhanced proliferation of colonic epithelial cells and reduced apoptosis of the colonic mucosa were observed in patients with acromegaly. […] The IGF-I/IGF-IR system also plays an important role in the promotion of cell adhesion, migration, and tumor microenvironment including the angiogenesis in the tumor. […] Excessive GH leads to cell survival with downregulation of tumor suppressor genes such as p53 and APC, which results in neoplastic colon growth. […] GH suppressed DNA damage response (DDR) by inhibiting phosphorylated ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (Chk2), and p53. […] These mechanisms were observed independent of IGF-I action.

• #24 The effect of acromegaly on thyroid disease

  https://www.jstage.jst.go.jp/article/endocrj/70/11/70_EJ23-0356/_html/-char/en

  Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). […] Most studies have indicated that the long-term stimulation of the follicular epithelium by GH and IGF-1 can lead to thyroid dysfunction, goiter, thyroid nodules, thyroid cancer, and thyroid-associated ophthalmopathy (TAO). […] Long-term stimulation of the thyroid follicular epithelium by high GH and IGF-1 can cause thyroid dysfunction, benign hyperplasia (including goiter and thyroid nodules), and even thyroid cancer. […] Scholars have proposed different mechanisms to explain the effect of high GH/IGF-1 levels on thyroid functions, especially TSH.

• #25 Frontiers | Molecular targets in acromegaly

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1068061/full

  Molecular therapeutic targets in growth hormone (GH)-secreting adenomas range from well-characterized surface receptors that recognize approved drugs, to surface and intracellular markers that are potential candidates for new drug development. […] The underlying pathogenesis likely involves disruption of cell-cycle control, alteration of signaling pathways, genetic/epigenetic changes, and abnormal hormone production. […] Tumorigenesis involves dysregulation of cell proliferation and GH production through transcriptional, hormonal, and other growth stimulating factors. […] Activating GNAS (guanine nucleotide binding protein, alpha stimulating activity polypeptide 1 gene) mutations, present in up to 40% of sporadic tumors, leads to constitutive cAMP activation and consequent excess GH production.

• #26 Acromegaly medications (Mechanism of Action) – My Endo Consult

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

  Somatostatin analogs (SSAs) are a class of drugs that bind to and activate somatostatin receptors (SSTRs). Somatostatin is a naturally occurring hormone that inhibits the secretion of growth hormone (GH) from the somatotroph cells in the pituitary gland. […] Pegvisomant is a relatively new medication used in the treatment of acromegaly, pegvisomants mechanism of action is unique in that it targets the growth hormone receptor (GHR) directly. pegvisomant structurally mimics growth hormone (GH), allowing it to bind and occupy the GH receptor pocket. This prevents GH from binding and activating the GHR, thus halting the downstream signaling cascade that leads to cell proliferation. Additionally, pegvisomant does not activate the GHR itself (termed an antagonistic action), rather it induces defective dimerization of the receptor, preventing subsequent signal transduction pathways.

• #27 Practical guidelines for diagnosis and treatment of acromegaly | Endocrinología y Nutrición (English Edition)

  https://www.elsevier.es/pt-revista-endocrinologia-nutricion-english-edition–412-articulo-practical-guidelines-for-diagnosis-treatment-S2173509313001670

  Acromegaly and gigantism are due to excess GH secretion, usually by a pituitary adenoma. It is an uncommon disease. […] Somatotroph adenomas are of monoclonal origin and develop from genetic changes. Hypothalamic and paracrine GHRH and somatostatin, like growth factors, promote the expansion of tumoral somatotroph cells. […] More than 90% of patients with acromegaly have a monoclonal benign pituitary adenoma surrounded by non-hyperplastic pituitary tissue. […] Excess GHRH production of hypothalamic (usually gangliocytomas) or peripheral central origin may lead to somatotroph cell hyperplasia and acromegaly. […] SSAs, like native somatostatin itself, have an inhibitory action on GH secretion. The currently available SSAs, octreotide and lanreotide, mainly act through subtype 2 receptors and to a lesser extent on subtype 5 receptors.

• #28 Acromegaly: Pathophysiological Considerations and Treatment Options Including the Evolving Role of Oral Somatostatin Analogs

  https://www.mdpi.com/1873-149X/30/3/29

  The first-line pharmaceutical approach to the treatment of acromegaly is the somatostatin analog class of drugs which mimic the physiological actions of somatostatin. The cyclic polypeptide somatostatin acts as one of the primary inhibitors of endocrine and exocrine hormone secretion with suppressive effects on a variety of hormones, including GH and anti-proliferative effects, reversing the impact of IGF-1’s mitogenic signals. Native somatostatin is extremely clinically limited due to its 1–3 min half-life and rapid degradation by peptidases in plasma and tissues. Somatostatin induces its biological effects via a subset of G protein couple receptors (SSTR1-SSTR5). […] Mycapssa, an oral octreotide capsule for treating acromegaly, received FDA approval in 2020 and provides an alternative method of drug administration that may prove more convenient than the standard subcutaneous or intramuscular injections of octreotide. Octreotide, a synthetic version of somatostatin, is a somatostatin analog drug class member. Somatostatin analogs have proven effective in suppressing GH secretion by the pituitary gland and pituitary adenomas, as well as efficacy in suppressing hepatocyte IGF-1 production and in arresting tumor growth. For these reasons, somatostatin analogs remain the far and away first-line medical treatment of acromegaly with support for treatment efficacy in patients before surgery, post-surgery, and in cases where surgery is not an option for treatment.

• #29 Practical guidelines for diagnosis and treatment of acromegaly | Endocrinología y Nutrición (English Edition)

  https://www.elsevier.es/pt-revista-endocrinologia-nutricion-english-edition–412-articulo-practical-guidelines-for-diagnosis-treatment-S2173509313001670

  The action of SSAs is mainly mediated through subunit G, inhibiting adenyl cyclase and decreasing cAMP generation. They also regulate tyrosine phosphatase activity and calcium and potassium channels. […] Pegvisomant (PEG), the only GH antagonist, is a 199-amino acid pegylated product obtained by genetic recombination in Escherichia coli that behaves as a selective GH receptor antagonist. The substitution of glycine 120 in the third helix chain of the GH molecule interferes with the second binding to the receptor. […] Pegvisomant does not suppress dimerization, and the GHR complex is internalized, but is unable to produce an intracellular transduction signal.

• #30 Pasireotide: a novel treatment for patients with acromegaly | DDDT

  https://www.dovepress.com/pasireotide-a-novel-treatment-for-patients-with-acromegaly-peer-reviewed-fulltext-article-DDDT

  However, the desensitization of SSTRs in patients with acromegaly who respond well to SRLs shows a persistent inhibitory effect of GH secretion without escape after prolonged treatment periods. […] Pasireotide modulates SSTR trafficking differently than octreotide, resulting in quicker recycling of SSTRs, particularly SSTR2, to the plasma membrane after endocytosis. […] In contrast to receptor desensitization, the expression of SSTRs is highly variable in pituitary adenomas. […] The expression of SSTR2 mRNA expression correlates positively with in vivo GH suppression induced by SRLs. […] However, the loss of SSTR2 is not the only determinant. […] Some partially SRL-sensitive GH-secreting adenomas have a loss of SSTR2 expression. […] Therefore, some GH-secreting adenomas show better response to SSTR2-specific ligands, while in others, SSTR5-specific ligands are more potent.

• #31 Mechanism of Action | Pfizer for Professionals

  https://somavert.pfizerpro.com/about/moa

  SOMAVERT has a distinct mechanism of action to help normalize IGF-I levels. […] SOMAVERT is the only GH receptor antagonist for acromegaly. […] SOMAVERT works by blocking GH receptors, therefore reducing IGF-I production. […] SOMAVERT was designed to directly antagonize GH activity in the liver and act independently of pituitary tumor SSTR expression.

• #32 Acromegaly – My Endo Consult

  https://myendoconsult.com/learn/acromegaly/

  Pegvisomant’s mechanism of action is unique in that it targets the growth hormone receptor (GHR) directly. Pegvisomant structurally mimics growth hormone (GH), allowing it to bind and occupy the GH receptor pocket. This prevents GH from binding and activating the GHR, thus halting the downstream signaling cascade that leads to cell proliferation. Additionally, pegvisomant does not activate the GHR itself (termed an antagonistic action), rather it induces defective dimerization of the receptor, preventing subsequent signal transduction pathways. […] There are several potential mechanisms of somatostatin analog resistance, including decreased somatostatin receptor expression and somatostatin receptor mutations.

• #33 Novel therapies for acromegaly in: Endocrine Connections Volume 9 Issue 12 (2020)

  https://ec.bioscientifica.com/view/journals/ec/9/12/EC-20-0433.xml

  In recent years, novel therapies have been studied in preclinical and clinical trials, and in the year 2020, one of them was approved for clinical treatment. […] While some of them correspond to new therapeutic agents, others represent new SRLs with different routes of administration or even a novel combination of already existing drugs. […] ATL1103 is an antisense oligomer drug designed to block GHR expression, thereby lowering IGF-I levels. […] ATL1103 forms a complex with GHR mRNA and activates RNase H, which cleaves this hybrid, degrading GHR mRNA and preventing gene transcription. […] The current findings of ATL1103 demonstrate a proof of concept that GH-receptor antisense oligomer lowers IGF-I levels in acromegaly.

• #34 Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine | Nature Communications

  https://www.nature.com/articles/s41467-023-36673-z

  Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. […] The first-generation drug octreotide is a biologically stable synthesized SST analog used for the treatment of acromegaly. […] However, ~30% of the acromegalic patients do not respond well to octreotide. […] After much effort has been made over years, an SSTR2 subtype-selective agonist paltusotine has recently been developed by Crinetics, which is an orally bioavailable non-peptide small molecule and is undergoing phase 3 trials for the clinical treatment of acromegaly and other NETs. […] SSTR2 transmits extracellular signals into cells through Gi/o coupling and -arrestin recruitment pathways. […] Previous clinical evidence showed that the expression level of SSTR2 occurred down-regulated during the administration of SST analog octreotide for acromegalic patients, and lower of -arrestin 1 in pituitary adenomas was associated with better drug efficacy.

• #35 Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine | Nature Communications

  https://www.nature.com/articles/s41467-023-36673-z

  Therefore, understanding of the pharmacological characteristics and molecular mechanism of different ligands, including peptide and small-molecule drugs, may help improve therapeutic strategies involving SSTR2 signaling. […] We find that the small molecule paltusotine possesses a better Gi-biased property compared with octreotide. […] Our findings provide insights into the molecular mechanism of the promising clinical small-molecule drug for the treatment of NETs. […] Paltusotine induced lower -arrestin recruitment compared with octreotide. […] We further explored the impact of the residues affecting the -arrestin signal on the internalization of SSTR2. […] Collectively, we mapped the signaling bias-related residues in the structure and found that within the octreotide extended region, I284ECL3, K2917.32, N2766.55, and F2947.35 in the extended region of octreotide contributed to activation of the -arrestin signal and the internalization of SSTR2 activated by octreotide. […] Whereas the downstream microswitch residues involved in the efficacy of -arrestin recruitment induced by both ligands.

• #36 Acromegaly: Pathophysiological Considerations and Treatment Options Including the Evolving Role of Oral Somatostatin Analogs

  https://www.mdpi.com/1873-149X/30/3/29

  Somatostatin analogs are a class of acromegaly-treating drugs that bind to somatostatin receptors and suppress GH release from both the pituitary gland and the somatotroph adenomas found in acromegaly. Somatostatin analogs are also effective in suppressing IGF-1 production due to the suppression of GH secretion and subsequently decreased binding of GH to hepatocytes. Mycapssa is an oral capsule formulation of octreotide, a synthetic octapeptide human somatostatin analog. Octreotide’s synthetic formulation has a half-life of approximately 100 min compared to 2–3 min for endogenous somatostatin in humans. Typically, octreotide exhibits low bioavailability with oral administration, therefore limiting treatment to the parenteral route. The greatest contributors to oral octreotide’s low bioavailability are its low enzymatic stability and poor membrane permeability within the lumen of the gastrointestinal tract. Octreotide capsules (Mycapssa) have overcome these limitations with a new formulation combining octreotide with other excipients to produce a transient permeation enhancer (TPE) technology. The TPE technology is produced by octreotide’s combination with excipients, yielding an oily suspension of hydrophilic particles in a lipophilic medium. This suspension can inflict transcellular perturbation of the intestinal epithelial barrier, which causes transient opening of the intestinal epithelial tight junctions. This TPE technology has been shown to effectively facilitate the paracellular transport of octreotide across the gastrointestinal wall into the small intestine.

• #37 Mortality in acromegaly: a 20-year follow-up study in: Endocrine-Related Cancer Volume 23 Issue 6 (2016)

  https://erc.bioscientifica.com/view/journals/erc/23/6/469.xml

  Excess growth hormone (GH) production in acromegaly leads to disadvantageous metabolic changes and comorbidities, such as hypertension, cardiovascular diseases, diabetes mellitus, respiratory system dysfunction and malignant neoplasms (Colao et al. 2004, Melmed 2006, Dekkers et al. 2008). […] In addition, it has been suggested that hypopituitarism (Tomlinson et al. 2001, Ayuk et al. 2004, Sherlock et al. 2010, Arosio et al. 2012) and radiotherapy (Ayuk et al. 2004, Holdaway et al. 2004, Dekkers et al. 2008, Sherlock et al. 2009, 2010, Arosio et al. 2012, Mercado et al. 2014) may impair overall prognosis. […] In the present study, older age at diagnosis independently predicted mortality. It is thus possible that a greater delay in the diagnosis of women with acromegaly contributes to the gender difference observed in mortality compared with the controls in the present study.

• #38 Acromegaly: What It Is, Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/17743-acromegaly

  If left untreated, acromegaly can cause the following complications: Type 2 diabetes, high blood pressure (hypertension), heart disease, cardiomyopathy (disease of your heart muscle), arthritis, colon polyps, which can potentially turn into colon cancer if left untreated, organ failure. […] Life expectancy for someone with acromegaly depends on the severity of the condition and if they have other health conditions, usually due to untreated acromegaly.

• #39 Pasireotide: a novel treatment for patients with acromegaly | DDDT

  https://www.dovepress.com/pasireotide-a-novel-treatment-for-patients-with-acromegaly-peer-reviewed-fulltext-article-DDDT

  Acromegaly is most commonly caused by a somatotroph pituitary adenoma with autonomous overproduction of growth hormone (GH). […] The excess GH causes increased transcription, synthesis, and release of insulin-like growth factor 1 (IGF-1) from the liver. […] If untreated, serious consequences such as diabetes mellitus, hypertension, sleep apnea, pulmonary hypertension, and heart failure can increase patients mortality by up to 2.5-3.5 times in comparison with the general population. […] Medical therapy, such as somatostatin receptor ligands (SRLs) and dopamine agonists or the GH-receptor antagonist pegvisomant target pituitary adenoma GH secretion or block peripheral GH action, respectively, and are mostly used to treat persistent or recurrent acromegaly after noncurative neurosurgery.

• #40

  https://reu.termedia.pl/Skeletal-complications-in-acromegaly,169918,0,2.html

  Hypersecretion of growth hormone (GH) is rare and typically results from a pituitary functional tumor somatotropinoma. It leads to excessive linear bone growth and manifests as gigantism if occurring in childhood and adolescence, before the closure of epiphyses or as a acromegaly in adulthood. The excess of GH impacts bone metabolism directly as well as indirectly through increased insulin-like growth factor1 (IGF-1). In acromegaly as a consequence of overproduction of GH and IFG-1 and the influence of these hormones on bone osteoblasts, bone metabolism, growth and density increase. […] However, bone turnover is accelerated causing impaired bone microstructure and strength, which may lead to increased risk of vertebral fractures irrespective of normal bone mineral density. […] Histomorphometric bone parameters analyzed in acromegalic patients with VFs and normal BMD showed increased cortical thickness and porosity and reduced trabecular thickness with increased trabecular separation compared to healthy control subjects. […] The GH and IGF-1 excess in acromegaly has a deleterious impact on skeletal health and increases VFs and OA risk. The changes are partially irreversible despite achieving biochemical remission of acromegaly.

• #41 Insulin-Like Growth Factor 1 as a Pillar in Acromegaly: From Diagnosis to Long-Term Management

  https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2024.2096

  Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH) and its peripheral target, hormone insulin-like growth factor 1 (IGF-1), with most cases of acromegaly caused by GH-secreting pituitary tumors. […] The primary goal of treatment is normalization of IGF-1 and GH concentrations, with additional goals including minimization of tumor growth, symptom relief, management of complications and improved patient QoL. […] Early detection and treatment of acromegaly are hindered by the slow, insidious development of clinical features over decades, with the resultant physical changes unnoticed by patients, family members and physicians, thus delaying diagnosis. […] Although GH concentrations diagnostic of acromegaly are dependent on the assays performed, reduced GH after OGTT has been considered the gold standard, both for diagnosis and the determination of biochemical remission.

• #42 Gigantism and Acromegaly – Endocrine and Metabolic Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/pituitary-disorders/gigantism-and-acromegaly

  Reduction of IGF-I and GH levels to the normal range seems to reduce mortality rates to normal. […] Somatostatin receptor ligands are a mainstay of therapy because they decrease GH secretion from the pituitary tumor mediated through interactions predominately with the somatostatin subtype receptor-2 (SSTR-2). […] Pegvisomant, the GH receptor antagonist, is given as a daily subcutaneous injection and decreases IGF-I levels and symptoms but does not decrease GH levels or act on the pituitary tumor.

• #43 Novel therapies for acromegaly in: Endocrine Connections Volume 9 Issue 12 (2020)

  https://ec.bioscientifica.com/view/journals/ec/9/12/EC-20-0433.xml

  Acromegaly is a chronic systemic rare disease most commonly caused by a somatotroph pituitary adenoma with autonomous overproduction of growth hormone (GH) and a consequent increase in insulin-like growth factor type I (IGF-I) levels produced mainly by the liver. […] If left untreated, acromegaly results in an increased morbi-mortality with a significant decrease in quality of life and an average 10-year reduction in life expectancy. […] Disease control by reducing GH to 1 g/L and normalizing IGF-I restores mortality to normal rates of the general population. […] In addition to biochemical control, treatment aims to prevent tumor growth or, ideally, induce tumor shrinkage. […] Currently, treatment of acromegaly includes neurosurgery, medical therapy and radiotherapy. […] The current clinical management of acromegaly is far from ideal, since biochemical control is not achieved in all patients; adverse events may be critical in some individuals, leading to intolerance and limited use; and except for DA, all frequently used drugs require regular injections, which could reduce the quality of life.

• #44 Acromegaly – Symptoms, Causes, Images, and Treatment Options

  https://www.epocrates.com/online/diseases/522/acromegaly

  Acromegaly is a rare, chronic disease caused by excessive secretion of growth hormone (GH), usually due to a pituitary somatotroph adenoma. It is associated with increased morbidity and premature mortality if not appropriately treated. […] Modern surgical and pharmacologic modalities are associated with improved outcomes. Normalization of plasma insulin-like growth factor 1 (IGF-1) and a decrease of plasma GH to below 1 microgram/L bring the mortality rate to normal. […] Monitoring and treatment of the comorbidities associated with acromegaly are essential for improving patient quality of life.

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