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)

Pituitary diseases are relatively common entities in the general population. They include pituitary adenomas and hypopituitarism. Pituitary tumours can cause symptoms of mass effect and hormonal hypersecretion that can be reversed with surgical resection or debulking of the adenoma, radiotherapy, or medical treatment. Transsphenoidal adenomectomy is the treatment of choice for acromegaly, Cushing's disease, gonadotropin-secreting tumours; and thyrotropin (TSH)-secreting adenomas. Pituitary irradiation and medical therapy are secondary options. Conversely, medical treatment is the primary choice for prolactinomas. Dopamine agonists are very effective in the treatment of prolactin (PRL)-secreting tumours, with rates of control as high as 80 to 90% for microprolactinomas (< 10 mm) and 60 to 75% for macroprolactinomas (> or = 10 mm). Somatostatin analogues have also shown efficacy in patients with acromegaly who have not responded to surgery or in patients with TSH-secreting adenomas who have not improved with surgery and radiotherapy. In patients with Cushing's disease, who are not cured surgically or who relapse after pituitary adenomectomy and irradiation, steroidogenic inhibitors can be an efficient method of controlling the hypercortisolism. Pituitary insufficiency is the partial or complete loss of the anterior hypophyseal function, which is due to hypothalamic or pituitary disease. Although the classic sequence of loss of pituitary secretion is growth hormone (GH), gonadotropins, TSH, and corticotropin (ACTH), the order to begin the replacement therapy of the deficient hormone(s) is cortisol, thyroxine, androgens/estrogens and, if necessary, GH. There are multiple preparations that can be used to achieve clinical and biochemical improvement. In general, the hormone replacement therapy is lifelong.
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PMID:Pituitary disorders. Drug treatment options. 1071 1

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5-1.0 microg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D(2) receptors using specific radiotracers such as (123)I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing's disease or Nelson's syndrome.
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PMID:New medical approaches in pituitary adenomas. 1097 Nov 10

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulate food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.
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PMID:Biologic activities of growth hormone secretagogues in humans. 1132 6

Somatostatin analogues are widely employed in the treatment of hypophyseal adenomas. The most widely used analogues at the present time are octreotide and lanreotide. Both are available in slow release formulations using the parenteral route and show a preferential affinity for the sst(2) receptor of somatostatin. Both octreotide and lanreotide have proved their effectiveness in the treatment of GH- and TSH-secretory hypophyseal adenomas. In those patients who respond to pharmacological treatment we often achieve not only the control of hormonal hypersecretion, but also a reduction in the volume of hypophyseal neoplasia. In the other types of hypophyseal adenoma, on the other hand, somatostatin analogues have proved to have little effect: apart from isolated cases of effectiveness in non-functioning adenomas, the administration both of octreotide and lanreotide to patients with Cushing's disease or prolactinoma did not significantly modify the hormonal hypersecretion or tumoural volume. The side-effects of somatostatin analogues are comparatively rare and of moderate entity: only a small percentage of patients requires the treatment to be suspended owing to the occurrence of side-effects. New analogues are currently under study. These have a different receptor profile and they could therefore find new applications in hypophyseal pathology. Octreotide, bound to radioactive substances or to toxins, has also been utilised for the selective destruction of neoplastic tissues expressing the sst(2) receptor of somatostatin.
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PMID:[The role of somatostatin analogues in the treatment of hypophyseal adenomas]. 1262 62

Surgical excision of an ACTH-producing pituitary tumor is the optimal therapy for Cushing's disease. However, medical therapy may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. When medication is the only therapy, a major disadvantage is the need for lifelong therapy; in general, recurrence follows discontinuation of treatment. These compounds work through three broad mechanisms of action. "Neuromodulatory" compounds modulate corticotropin (ACTH) release from a pituitary tumor, steroidogenesis inhibitors reduce cortisol levels by adrenolytic activity and/or direct enzymatic inhibition and glucocorticoid antagonists block cortisol action at its receptor. In general, neuromodulatory compounds (bromocriptine, cyproheptidine, somatostatin and valproic acid) are not very effective agents for Cushing's disease. Treatment with a glucocorticoid antagonist and radiation therapy has been reported on a single patient only. Steroidogenesis inhibitors, including mitotane, metyrapone, ketoconazole, and aminoglutethimide, are the agents of choice for medical therapy of Cushing's disease. In general, ketoconazole is the best tolerated of these agents and is effective as monotherapy in about 70% of patients. Mitotane and metyrapone may be effective as single agents, while aminoglutethimide generally must be given in combination. The intravenously-administered etomidate may used when patients cannot take medications by mouth.
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PMID:Medical therapy of Cushing's disease. 1267 4

The development of efficacious surgical and medical therapies for pituitary adenomas as well as the improvement of hormone therapy for ovulation induction has made pregnancy possible for women harboring pituitary tumors. However, gestational risks due to the possibility of tumor growth during pregnancy, mainly in women with macroadenomas, raise a concern. Bromocriptine has a well-established role for prolactinoma treatment before and during pregnancy, even when a symptomatic tumor increase occurs. It can also be used in acromegaly, despite its poorer results. Somatostatin analogs have been used in acromegaly even during pregnancy with uneventful outcomes, but their safety in pregnancy is not well established, yet. The largest experience with medical treatment for Cushing's disease during pregnancy involves metyrapone, a steroidogenesis inhibitor, without descriptions of congenital abnormalities. Concerning clinically non-functioning pituitary tumors, ovulation induction or even in vitro fertilization are frequently needed. The purpose of this review is to provide an update on therapeutic strategies to restore fertility as well as gestational and post-gestational management of patients with pituitary adenomas, focusing mainly on the role of medical treatment for different tumor types.
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PMID:Medical management of pituitary adenomas: the special case of management of the pregnant woman. 1267 7

Medical therapy with a dopamine agonist is the most effective for treatment of a prolactin-producing adenoma and is considered as primary treatment. Surgery and pituitary radiation are reserved for patients who either do not tolerate or do not respond to a dopamine agonist drug. A somatostatin analogue is effective medical therapy for patients with acromegaly, and this is usually administered if there is persistent GH hypersecretion after surgical resection. Medical treatment for patients with Cushing's disease is directed at the adrenal glands to reduce cortisol hypersecretion. Unfortunately, there is no effective medical therapy to reduce pituitary corticotropin production. Medical therapy for a gonadotrope adenoma with a dopamine agonist or somatostatin analogue has limited utility but is employed in patients who are unable to undergo surgery and may delay or prevent additional tumor growth. Many patients with a pituitary adenoma can be successfully treated with one treatment, either a dopamine agonist for a prolactinoma or surgery for other types of tumors. A substantial number of patients require multimodality therapy, however, including medical therapy, surgery, and pituitary radiation. Because the biologic behavior of pituitary adenomas varies considerably, a patient with a pituitary adenoma requires lifelong regular monitoring for hormone hypersecretion, tumor recurrence, and development of new pituitary hormone deficiency. A coordinated plan of care among endocrinologists, neurosurgeons, neuroophthalmologists, and radiation therapists is necessary to provide optimal care for these patients.
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PMID:Medical treatment of functional pituitary tumors. 1269 Sep 80

In a series of human corticotroph adenomas, we recently found predominant mRNA expression of somatostatin (SS) receptor subtype 5 (sst5). After 72 h, the multiligand SS analog SOM230, which has a very high sst5 binding affinity, but not Octreotide (OCT), significantly inhibited basal ACTH release. To further explore the role of sst5 in the regulation of ACTH release, we conducted additional studies with mouse AtT-20 cells. SOM230 showed a 7-fold higher ligand binding affinity and a 19-fold higher potency in stimulating guanosine 5'-O-(3-thiotriphosphate) binding in AtT-20 cell membranes compared with OCT. SOM230 potently suppressed CRH-induced ACTH release, which was not affected by 48-h dexamethasone (DEX) pretreatment. However, DEX attenuated the inhibitory effects of OCT on ACTH release, whereas it increased the inhibitory potency of BIM-23268, an sst5-specific analog, on ACTH release. Quantitative PCR analysis showed that DEX lowered sst(2A+2B) mRNA expression significantly after 24 and 48 h, whereas sst5 mRNA levels were not significantly affected by DEX treatment. Moreover, Scatchard analyses showed that DEX suppressed maximum binding capacity (B(max)) by 72% when 125I-Tyr3-labeled OCT was used as radioligand, whereas B(max) declined only by 17% when AtT-20 cells were treated with [125I-Tyr11]SS-14. These data suggest that the sst5 protein, compared with sst2, is more resistant to glucocorticoids. Finally, after SS analog preincubation, compared with OCT both SOM230 and BIM-23268 showed a significantly higher inhibitory effect on CRH-induced ACTH release. In conclusion, our data support the concept that the sst5 receptor might be a target for new therapeutic agents to treat Cushing's disease.
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PMID:Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. 1576 96

The successful treatment of Cushing syndrome depends on specific therapy directed against the etiology of hypercortisolism. In addition to surgical procedures, various drugs have been employed in the management of this difficult disease. Compounds with neuromodulatory properties have been effective in only a limited number of cases of hypothalamic-pituitary-dependent Cushing disease, the most common form of Cushing syndrome. These agents include serotonin antagonists (cyproheptadine, ketanserin, ritanserin), dopamine agonists (bromocriptine, cabergoline), GABA agonists (valproic acid [sodium valproate]), and somatostatin analogs (octreotide). Interesting new avenues at the pituitary level involve the potential use of thiazolidinedione compounds, such as rosiglitazone, and of retinoic acid, which are ligands of different nuclear hormone receptors involved in hypothalamic-pituitary regulation. The most exciting news, however, in the pharmacologic approach to Cushing syndrome refers to the adrenal corticotropin (adrenocorticotropic hormone; ACTH)-independent forms, in which aberrant adrenal receptors, through the binding of their respective ligands, could lead to chronic cortisol overproduction. They include receptors for gastric inhibitory peptide (GIP), beta-adrenergic agonists, luteinizing hormone (LH)/human chorionic gonadotropin, serotonin (5-HT(4) receptor), vasopressin (V(1) receptor), and angiotensin II (AT(1) receptor). In GIP-dependent Cushing syndrome, the most frequent subtype of ACTH-independent macronodular adrenal hyperplasia associated with the presence of aberrant adrenocortical hormone receptors described so far, octreotide administration before each meal showed clinical efficacy only in the first few months, probably because of somatostatin receptor downregulation in GIP-secreting cells. Long-term medical treatments with propranolol and the gonadotropin-releasing hormone analog leuprorelin (leuprolide acetate) were effective in patients with catecholamine-dependent and LH-dependent Cushing syndrome, respectively. The oral vasopressin V(1) receptor antagonist OPC-21268 and the angiotensin II (AT(1)) receptor antagonist candesartan cilexetil were also able to decrease cortisol levels during the few days of administration of the drugs in patients with specific receptor abnormalities. These adrenal forms of Cushing syndrome are rare, and clinical data are scarce. Moreover, the real clinical significance of aberrant hormone receptors is still under investigation, as is the possibility of avoiding surgery by pharmacologic manipulation. Patients in whom these intriguing syndromes are suspected require detailed investigation protocols, which should be carried out in specialized centers. While awaiting further developments, the use of traditional medical treatment at the adrenal level with adrenal steroid inhibitors is still valuable in several instances.
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PMID:Pharmacologic management of Cushing syndrome : new targets for therapy. 1578 46

Somatostatin (SRIF) has been proposed to be of therapeutic interest in the medical treatment of Cushing's disease. While in vitro data demonstrate the presence of SRIF-receptor subtype (sst) expression in corticotroph adenomas, the current clinically available SRIF-analog Octreotide, predominantly targeting sst(2), is ineffective in lowering ACTH levels in Cushing's disease and only appears to inhibit the release of ACTH in Nelson's syndrome. In the present review, current knowledge on the physiological role of SRIF in the regulation of ACTH secretion by the anterior pituitary gland, as well as by corticotroph tumor cells is summarized. In addition, the role of glucocorticoids in regulating sst-mediated inhibition of ACTH release by corticotroph adenoma cells is discussed. Recently, it was reported that the novel multiligand SRIF-analog SOM230 might have the potential to be of therapeutic interest for Cushing's disease. On the basis of the potent suppressive effects on ACTH release by SRIF-analogs with high binding affinity to sst(5) and the observation that sst(5) expression and action is relatively resistant to glucocorticoid treatment, including the recent observation that sst(5) is the predominant sst expressed in human corticotroph adenomas, it is hypothesized that sst(5) may be a new therapeutic target for the control of ACTH and cortisol hypersecretion in patients with pituitary dependent Cushing's disease.
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PMID:The role of somatostatin analogs in Cushing's disease. 1613 2


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