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, a chronic disease of growth hormone (GH) hypersecretion, is most typically caused by a pituitary adenoma. Early diagnosis is critical for prompt intervention to prevent deleterious effects of prolonged exposure to elevated GH and insulin-like growth factor Type I (IGF-I) levels. Current therapy for acromegaly includes several options: surgery, radiotherapy and pharmacotherapy. Transsphenoidal adenomectomy remains a mainstay of therapy for acromegaly. Cure rates are high in microadenomas, but < 50% in macroadenomas. Conventional and stereotactic procedures for radiation therapy are also effective in decreasing GH levels in acromegalic patients, but they need years to normalise GH hypersecretion and carry with them the risk of hypopituitarism. The major classes of drugs currently used to treat acromegaly are dopamine agonists and analogues of somatostatin. Dopamine agonists bind to the D2 receptor and suppress GH hypersecretion in some patients with acromegaly. Their clinical effectiveness is modest, although promising results have been obtained with two novel compounds, quinagolide and cabergoline, that possess long duration of action. Somatostatin analogues have been shown to improve clinical symptoms of acromegaly, decrease hypersecretion of GH and IGF-I and reduce tumour volume in a clinically significant number of patients. Octreotide is administered by s.c. route several times a day, but the recently developed sustained release formulations (octreotide LAR and SR lanreotide) are administered only every 7-28 days by i.m. injections. The complications associated with somatostatin analogues are small, relative to the benefits. Lastly, compounds with a novel mechanism of action, the GH receptor antagonists, are presently under investigation.
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PMID:Current management of acromegaly. 1124 4

Growth hormone (GH) is essential for postnatal somatic growth, maintenance of lean tissue at maturity in domestic animals and milk production in cows. This review focuses on neuroregulation of GH secretion in domestic animals. Two hormones principally regulate the secretion of GH: growth hormone-releasing hormone (GHRH) stimulates, while somatostatin (SS) inhibits the secretion of GH. A long-standing hypothesis proposes that alternate secretion of GHRH and SS regulate episodic secretion of GH. However, measurement of GHRH and SS in hypophysial-portal blood of unanesthetized sheep and swine shows that episodic secretion of GHRH and SS do not account for all episodes of GH secreted. Furthermore, the activity of GHRH and SS neurons decreases after steers have eaten a meal offered for a 2-h period each day (meal-feeding) and this corresponds with reduced secretion of GH. Together, these data suggest that other factors also regulate the secretion of GH. Several neurotransmitters have been implicated in this regard. Thyrotropin-releasing hormone, serotonin and gamma-aminobutyric acid stimulate the secretion of GH at somatotropes. Growth hormone releasing peptide-6 overcomes feeding-induced refractoriness of somatotropes to GHRH and stimulates the secretion of GHRH. Norepinephrine reduces the activity of SS neurons and stimulates the secretion of GHRH via alpha(2)-adrenergic receptors. N-methyl-D,L-aspartate and leptin stimulate the secretion of GHRH, while neuropeptide Y stimulates the secretion of GHRH and SS. Activation of muscarinic receptors decreases the secretion of SS. Dopamine stimulates the secretion of SS via D1 receptors and inhibits the secretion of GH from somatotropes via D2 receptors. Thus, many neuroendocrine factors regulate the secretion of GH in livestock via altering secretion of GHRH and/or SS, communicating between GHRH and SS neurons, or acting independently at somatotropes to coordinate the secretion of GH.
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PMID:Neuroregulation of growth hormone secretion in domestic animals. 1131 46

Tumor growth depends on several factors, including angiogenesis. Tumors cannot grow if new vessels are not formed to supply the cells with oxygen and other nutrients and to remove waste products. Increased angiogenesis can be correlated with tumor growth and metastatic potential in many tumor types, indicating that neoformation of vessels is a prognostic indicator of tumor behavior. We evaluated microvessel densities in 157 various pituitary adenoma types and seven pituitary carcinomas using immunocytochemistry for CD-34 antigen, a reliable marker of endothelial cells. The lowest percentage of microvessel density was found in growth hormone-producing adenomas, the highest level in pituitary carcinomas. In general, no major correlation was found between MIB-1 index (an indicator of cell proliferation) and microvessel density. The statistical study also demonstrated no gender-dependent changes in the microvessel density of pituitary tumors. Although the microvessel density was not significantly different in relation to invasiveness of pituitary tumors, our results demonstrate a tendency of invasive pituitary tumors to be more highly vascularized than non-invasive ones. Dopamine agonist and long-acting somatostatin analog treatment compared with untreated tumors did not significantly affect microvessel densities. Statistical differences were demonstrated in the microvessel density of macroadenomas between patients older and patients younger than 40 years. Significant differences were also apparent in the microvessel densities between microadenomas and macroadenomas diagnosed in young patients but not in the older age group. The strongly positive correlation observed between microvessel density and age is consistent with the view that age of the host may have an influence on the extent of neovascularization of pituitary adenomas.
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PMID:Microvessel density in pituitary adenomas and carcinomas. 1146 92

Dopamine and somatostatin have been implicated in the pathophysiology of depression. We have employed in vivo microdialysis to investigate the regulation of dopamine release by somatostatin in the nucleus accumbens and the striatum of awake, freely moving rats, and to ascertain how this regulation may be affected by desipramine treatment. Somatostatin-14 (10(-4) M) infusion induced an increase in the release of dopamine and a decrease in the release of its metabolites in both the nucleus accumbens (568% of basal) and the striatum (546% of basal). Chronic desipramine treatment resulted in an exaggerated somatostatin-induced increase of dopamine levels, specifically in the nucleus accumbens (3542% compared with 564% of basal in the striatum), whereas acute desipramine treatment had no effect (582% of basal) compared with saline treated rats. Basal concentrations of dopamine and metabolites were not influenced by either chronic or acute treatment of desipramine in either brain area. These results demonstrate that somatostatin regulates dopamine release in the nucleus accumbens and the striatum. Chronic antidepressant treatment influences somatostatin's actions on dopamine function selectively in the nucleus accumbens.
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PMID:Chronic desipramine treatment selectively potentiates somatostatin-induced dopamine release in the nucleus accumbens. 1155 1

The primary aim of therapy should be to remove symptoms, reduce tumor bulk, prevent relapse, and improve long-term outcome. Surgery, radiotherapy and medical therapies are used to achieve these aims. Post-treatment mean "safe" serum growth hormone values of < 2.5 ng/ml should be the therapeutic goal. Transsphenoidal surgery remains the first line treatment for acromegaly. Patients with microadenoma can expect 85%, while those with macroadenoma 50% chance to achieve safe serum growth hormone levels. Less than 20% of acromegalics respond to treatment with bromocriptine, while quinagolide and cabergoline may show better clinical response; the success rate is higher for tumors secreting both growth hormone and prolactin. Dopamine agonists may be considered either in combination with somatostatin-analogues or as monotherapy in selected patients, and in those with co-secretion of prolactin. Octreotide (Sandostatin, Novartis) is a synthetic somatostatin-analogue, which is administered subcutaneously in doses between 100 and 250 micrograms 3 times daily. Long-acting octreotide (Sandostatin LAR, Novartis) contains octreotide incorporated into microspheres of biodegradable polymer. To effectively lower serum growth hormone levels, monthly injections of 10-30 mg of long-acting octreotide are needed, serum growth hormone falls to 2.5 ng/ml in 70% of cases, and serum insulin-like growth factor I normalizes in 67%. Slow release lanreotide (Somatuline SR, Ipsen) is an alternative depot long-acting somatostatin-analogue, which is administered in a dose of 30 mg intramuscularly every 14, 10 or 7 days. Both compounds are equally, if not more, effective than subcutaneous octreotide, and significantly improve patient compliance. Pegvisomant (Sensus Drug Development Corporation) is a genetically engineered growth hormone receptor antagonist, which inhibits growth hormone action. When given subcutaneously in a dose of 20 mg/day, serum insulin-like growth factor I levels return to normal in 90% of patients. Theoretical concerns of tumor expansion have not been a problem to date, but long term studies are needed. Primary medical--somatostatin-analogue--therapy is recommended if surgery fails, if the patient refuses or unsuited for surgery and it may be also considered in patients with macroadenoma with extra--but not suprasellar extension, since the surgical "cure" rates of these tumors are low.
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PMID:[Novel pharmacologic therapies in acromegaly]. 1206 60

Dopamine is the primary inhibitory regulator of lactotroph proliferation and prolactin (PRL) secretion in vivo, acting via dopamine D2 receptors (short D2S and long D2L forms). In GH4C1 pituitary cells transfected with D2S or D2L receptor cDNA, dopamine inhibits PRL secretion and DNA synthesis. These actions were blocked by pertussis toxin, implicating G(i)/G(o) proteins. To address roles of specific G(i)/G(o)4 proteins in these actions a series of GH4C1 cell lines specifically depleted of individual Galpha subunits was examined. D2S-mediated inhibition of BayK8644-stimulated PRL secretion was primarily dependent on G(o) over G(i), as observed for BayK8644-induced calcium influx. By contrast, inhibitory coupling of the D2S receptor to TRH-induced PRL secretion was partially impaired by depletion of any single G protein, but especially G(i)3. Inhibitory coupling of D2L receptors to PRL secretion required G(o), but not G(i)2, muscarinic receptor coupling was resistant to depletion of any G(i)/G(o) protein, whereas the 5-HT1A and somatostatin receptors required G(i)2 or G(i)3 for coupling. The various receptors also demonstrated distinct G protein requirements for inhibition of DNA synthesis: depletion of any G(i)/G(o) subunit completely uncoupled the D2S receptor, the D2L receptor was uncoupled by depletion of G(i)2, and muscarinic and somatostatin receptors were resistant to depletion of G(i)2 only. These results demonstrate distinct receptor-G protein preferences for inhibition of TRH-induced PRL secretion and DNA synthesis.
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PMID:G protein preferences for dopamine D2 inhibition of prolactin secretion and DNA synthesis in GH4 pituitary cells. 1214 43

Dopamine is one of the principal neurotransmitters in the basal ganglia, where it plays a critical role in motor control and cognitive function through its interactions with the specific dopamine receptors D1 to D5. Although the activities mediated by most dopamine receptor subtypes have already been determined, the role of the D5 receptor subtype in the basal ganglia has still not been established. Furthermore, it is often difficult to distinguish between dopamine D5 and D1 receptors as they are stimulated by the same ligands, and they have a similar molecular structure and pharmacology. In an effort to understand the differences between these two receptor subtypes, we have studied the distribution of neurons containing D5 receptors in the striatum, and their molecular phenotype. As a result, we show that the D5 receptor subtype is present in two different populations of striatal neurons, projection neurons and interneurons. Overall, the abundance of this receptor subtype in the striatum is low, particularly in striatal projection neurons of both the direct and indirect projection pathways. In contrast, the expression of D5 receptors in striatal interneurons (cholinergic, somatostatin- or parvalbumin-positive neurons) is high, while low to moderate expression was observed in calretinin-positive neurons. Our results demonstrate the presence of D5 receptors in all the striatal cell populations so far described, although at different intensities in each. The fact that a large number of striatal neurons express the D5 receptor subtype suggests that this receptor fulfils an important function in the process of integrating information in the striatum.
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PMID:Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor subtype. 1247 72

Medical therapy plays an important role in the management of acromegaly. Dopamine agonists and somatostatin analogs are two classes of drugs approved for this purpose worldwide. Pegvisomant, a growth hormone receptor antagonist, has recently been evaluated in clinical trials. Somatostatin analogs have been the mainstay of medical treatment during the last 10 yr with their acceptability enhanced by the development of depot preparations. Somatostatin analogs improve symptoms and signs of acromegaly in the majority, normalize IGF- 1 in up to 60%, and result in tumor shrinkage in up to half of patients. Dopamine agonists have modest efficacy and limited tolerability. They are more effective in mixed GH/prolactin-secreting tumors. Newer agonists with D2 receptor specificity have fewer side effects but are less efficacious than somatostatin analogs. The addition of a dopamine agonist to somatostatin analog therapy can result in greater biochemical control than with individual agents. Pegvisomant is the most effective drug treatment for acromegaly, but it is likely to have a major adjuvant role as its mechanism of action is not directed at the tumor. The availability of more effective and better tolerated drug therapies offers greater flexibility and individualization of therapy that will lead to improved patient care and disease control.
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PMID:Comparison of efficacy and tolerability of somatostatin analogs and other therapies for acromegaly. 1272 11

Currently available therapies for acromegaly are transsphenoidal surgery (TSS), radiotherapy (RT) and medical therapy with the dopamine agonists and somatostatin analogues. The goals of these therapies for acromegaly are to normalize excessive hormone secretion, thus normalizing serum levels of growth hormone (GH) and of insulin-like growth factors (IGF-I), to reduce the clinical signs and symptoms of acromegaly and to reduce tumor size in order to relieve any symptoms due to tumor mass effect. These goals should be accomplished while preserving pituitary function and with as few side effects as possible.TSS, the initial choice of therapy in most patients, is the most effective therapy at reducing the signs and symptoms of mass effect such as visual or neurological compromise. TSS is potentially curative, but the outcome is highly dependent on the tumor size, the degree of tumor invasion and the expertise of the surgeon. TSS can achieve biochemical control with normalization of IGF-I in 80-90% of patients with microadenomas and in 50-60% of those with macroadenomas. RT may be used as adjunctive therapy after unsuccessful surgery. RT can lower GH levels and normalize IGF-I levels, but there is a long lag time before this effect is achieved. Biochemical control is not achieved for 6-10 years after conventional fractionated RT; the time to clinical effect after gamma knife RT seems to be shorter. The most common complication after all forms of RT for acromegaly is the development of new hypopituitarism. Medical therapy has assumed the major role as adjunctive therapy of acromegaly. The dopamine agonists used for the therapy of acromegaly include bromocriptine, quinagolide and cabergoline. Cabergoline seems to be the most efficacious of the dopamine agonists for the treatment of acromegaly, with normalization of IGF-I being achieved in up to 35% of patients treated. Dopamine agonists are generally not effective at reducing the size of pure GH-secreting pituitary tumors. Somatostatin analogues are the most effective medical therapy currently available for acromegaly. The clinically available long-acting somatostatin analogues are long-acting octreotide and slow-release lanreotide. Overall, IGF-I levels normalize in about 66% of patients treated with long-acting octreotide and in 48% of patients treated with lanreotide. About 30% of GH-secreting tumors treated with somatostatin analogues as adjunctive therapy will have some shrinkage, and the amount of shrinkage usually ranges between 20 and 50% of tumor size. Signs and symptoms of the disease improve in about two-thirds of patients treated with long-acting somatostatin analogues. Gastrointestinal side effects are common when initiating somatostatin analogue therapy, but these effects do not typically limit continued use. Multi-modality therapy for acromegaly is often needed to achieve disease control. However, even combinations of currently available therapies cannot achieve all the goals of therapy in many patients with acromegaly.
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PMID:How effective are current therapies for acromegaly? 1291 44

Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.
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PMID:Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. 1455 52


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