Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acromegaly is an endocrine disorder usually due to a growth hormone (GH)-secreting pituitary adenoma. This deforming disease is associated with several metabolic abnormalities and results in an elevated cardiovascular mortality. Pituitary transsesphenoidal surgery has been considered the treatment of choice, however, even in the most experienced hands this procedure succeeds in curing only 50 to 60% of the patients. Therefore, close to 50% of patients require an adjunctive form of treatment such as radiation therapy or the use of diverse medications that modulate GH secretion (somatostatin analogues) or action (GH receptor antagonists). The present review summarizes the clinical experience with these novel medications.
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PMID:[Pharmacological treatment of acromegaly]. 1702 8

This review summarizes current knowledge on pituitary changes in patients with acromegaly. The histologic, immunohistochemical and electron microscopic study provided conclusive evidence that a marked diversity exists between the tumors which secrete growth hormone (GH) in excess, such as densely and sparsely granulated GH cell adenoma, the mixed GH prolactin cell adenoma and the mammosomatotrope adenoma. The latter two tumors produce GH and prolactin simultaneously. Densely granulated GH cell tumors may produce thyrotropin and alpha subunit as well. Somatotrope carcinomas are extremely rare. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors. The medical therapy of acromegaly is reviewed briefly, including long-acting somatostatin analogs and pegvisomant, a GH receptor blocker.
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PMID:Pathology of acromegaly. 1704 79

The currently available long-acting somatostatin analogs normalize serum growth hormone (GH) levels and insulin-like growth factor-I levels in approximately 60% of patients with acromegaly. The recently introduced GH receptor antagonist, pegvisomant, is able to normalize insulin-like growth factor-I levels in virtually all acromegalic subjects. Although no correlation between increased GH concentrations and tumor size has been found, long-term safety studies are still in progress. Also, pegvisomant monotherapy is administered once daily and is very costly. Combined treatment of a somatostatin analog with pegvisomant appears to be an effective and rational approach.
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PMID:Growth hormone receptor antagonists. 1704 92

External radiotherapy (ideally 3-field radiotherapy with a daily fractional dose no higher than 1.8 Gy or conformal irradiation) has been used extensively in the treatment of acromegaly, and virtually all studies have documented a predictable but slow reduction in growth hormone (GH) excess, which is at its maximum in the first year after treatment (30-50%) and continues at an average rate of 10-15% thereafter in the long term. Therefore, achievement of 'safe' GH concentrations in an acceptable time interval after radiotherapy will be realized only in those patients who have lower GH concentrations prior to irradiation either as a result of mild disease or previous surgery. Recent studies have demonstrated the value of stereotactic radiotherapy (either as multiple arc X-irradiation or as 'gamma knife' therapy) in the post-surgical treatment of acromegaly or as salvage therapy for disease persisting after conventional external irradiation. The development of potent medical therapies for acromegaly (somatostatin analogues and the GH receptor antagonist) has called into question the role of radiotherapy in the treatment of this disease. However, even if the concept of primary, open-ended medical therapy for selected patients is accepted, reference to the success rates of surgery and response rates to somatostatin analogues indicates that approximately 10-20% of all patients with acromegaly will require consideration of radiotherapy for hormonal or tumour mass control. For these reasons, radiotherapy (both conventional external and stereotactic irradiation) continues to have a major role in controlling acromegaly in selected patients.
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PMID:Is there still a role for radiotherapy in acromegaly? 1704 93

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are implicated in the aberrant cell growth and pathological neovascularization that characterises proliferative diabetic retinopathy. While serum levels of IGF-I are reported to be either high or low in diabetic patients, there is evidence that local tissue levels of IGF-I may be more relevant to diabetic retinal pathology. IGF-I and IGF binding proteins (IGFBP) are expressed throughout the retina in vascular, neuronal and glial cells, and are altered in response to hyperglycaemia and hypoxia. Further support for a pathological role for local IGF-I comes from studies showing IGF-I to be increased in the vitreal fluids of patients with proliferative diabetic retinopathy. IGF-I may exert its cell growth promoting properties by stimulating a number of pathways including protein-kinase B (Akt), nuclear factor kB (NF-kappaB)/AP-1 and hypoxic-inducible factor-1alpha (HIF-1alpha). In addition, other growth factors may participate in IGF-I induced cell growth including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and fibroblast growth factor (FGF). The importance of the GH/IGF system in diabetic retinopathy and retinal neovascularization has been highlighted by the use of agents that inhibit the system. GH receptor antagonists, GH receptor antisense oligonucleotides, somatostatin analogues and receptor neutralising antibodies to IGF-I reduce hypoxic-induced retinal neovascularization. These approaches may also prove to have benefits for improving vascular patency and vision in patients with diabetic retinopathy.
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PMID:The role of growth hormone, insulin-like growth factor and somatostatin in diabetic retinopathy. 1716 53

Acromegaly is a rare condition usually caused by a GH secreting pituitary tumor. Rigorous control of the disease is important in order to bring the mortality rate on level with that of the background population. Surgery is first choice, and it is sufficient in 50-60% of the patients. Treatment with a somatostatin analogue is second choice and normalises GH hypersecretion in 60% of the patients; tumor shrinkage occurs in 30%. A newly developed GH receptor antagonist, pegvisomant, seems to offer complete suppression of GH activity in most patients and also improves glucose tolerance. The disadvantages of pegvisomant include lack of suppression of tumor activity and a high cost.
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PMID:[Acromegaly: new principles for treatment]. 1735 33

Pituitary tumors are a diverse group of neoplasms that are classified based on clinical manifestations, hormone excess, and histomorphologic features. Those that cause growth hormone (GH) excess and acromegaly are subdivided into morphologic variants that have not yet been shown to have pathogenetic significance or predictive value for therapy and outcome. Here, we identify a selective somatic histidine-to-leucine substitution in codon 49 of the extracellular domain of the GH receptor (GHR) in a morphologic subtype of human GH-producing pituitary tumors that is characterized by the presence of cytoskeletal aggresomes. This GHR mutation significantly impairs glycosylation-mediated receptor processing, maturation, ligand binding, and signaling. Pharmacologic GH antagonism recapitulates the morphologic phenotype of pituitary tumors from which this mutation was identified, inducing the formation of cytoskeletal keratin aggresomes. This novel GHR mutation provides evidence for impaired hormone autofeedback in the pathogenesis of these pituitary tumors. It explains the lack of responsiveness to somatostatin analogue therapy of this tumor type, in contrast to the exquisite sensitivity of tumors that lack aggresomes, and has therapeutic implications for the safety of GH antagonism as a therapeutic modality in acromegaly.
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PMID:A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors. 1767 Dec 21

The McCune-Albright syndrome is characterized by cafe-au-lait spots, precocious puberty and fibrous dysplasia. It is due to mutations in the gene encoding the Gs protein alpha subunit coupling 7-transmembrane-domain receptors to adenylate cyclase, leading to constitutive adenylate cyclase activation and cAMP overproduction. Endocrinologists, rheumatologists and gynecologists are confronted with new issues when these children reach adulthood. Dysplastic bone lesions seem to stabilize after puberty, but their disabling consequences (pain, fractures, etc.) may continue into adulthood. Gonadal function and fertility are often abnormal in women in whom puberty was precocious, owing to the persistence of a variable degree of ovarian autonomy that hinders adequate follicular development and ovulation. Acromegaly, when present, is often difficult to treat surgically because of skull-base dysplasia. Somatostatin analogs are only partially effective in most cases; fortunately, the GH receptor antagonist, pegvisomant may be more effective in normalizing IGF-I levels. Hyperthyroidism, generally due to multinodular toxic goiter, can be successfully treated by surgery or radioiodine administration. Recent data suggest that cancer incidence in adulthood (bone, breast, thyroid...) is increased in these patients.
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PMID:McCune-Albright syndrome in adulthood. 1798 95

Acromegaly is a chronic, debilitating disease caused by chronic growth hormone (GH) hypersecretion which results in chronic medical comorbidities, poor quality of life and high mortality rates. Successful treatment can improve clinical signs and symptoms and normalize mortality rates. Over 95% of acromegaly is caused by a somatotroph adenoma of the pituitary, and the first-line treatment is generally transsphenoidal surgery, which can be curative in 50-60% of patients. Nonetheless, high rates of persistent acromegaly following surgery and the limited efficacy of radiation therapy necessitate chronic medical treatment for many patients. Somatostatin analogues have become the preferred first-line medical therapy for many practitioners, as they achieve better biochemical and direct tumor control than the dopamine agonists, and long-acting preparations make once monthly administration possible. Cabergoline, a dopamine agonist, offers a lower-cost option and may be effective in patients with a pituitary tumor that co-secretes GH and prolactin. Pegvisomant is a GH receptor antagonist that produces exceptional biochemical response rates but lacks any direct effects on the tumor, which may limit its effectiveness as life-long monotherapy. Combinations of these three drug classes have not been rigorously studied, and preliminary trials do not suggest improved clinical outcomes. While medical treatment options for acromegaly have significantly improved over the last 30 years, limitations remain, and a multi-specialty team approach is necessary for the effective long-term management of patients with acromegaly.
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PMID:Management of acromegaly: is there a role for primary medical therapy? 1816 13

There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that when they are locally-produced within the mammary tissue, these hormones, acting by an autocrine-paracrine mechanism may have enhanced, or even specific functions compared to endocrine PRL and GH. Classical drugs blocking pituitary hormone production (dopamine and somatostatin analogs) are ineffective on extrapituitary expression of PRL/GH genes, therefore the undesirable effects of these locally-produced hormones remain a target of interest for alternative strategies. This has encouraged the development of competitive PRL and/or GH receptor antagonists, which involve engineered variants of natural receptor ligands (PRL or GH) aimed at blocking receptor activation rather than hormone production in peripheral tissues. This article overviews the rational design of this new class of molecules, their specific molecular features (receptor specificity, biological properties, etc.) and whenever available, the data that have been obtained in cell or animal models of breast cancer.
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PMID:Rational design of competitive prolactin/growth hormone receptor antagonists. 1821 65


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