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

A 33 year old woman was investigated for an atypical case of Cushing's syndrome with suppressed early morning plasma cortisols. Chronic hypercortisolism was confirmed by classical biological criteria (24 h urinary cortisol excretion, dexamethasone suppression tests); more detailed dynamic and pharmacological tests revealed unanticipated features: spontaneous circadian plasma cortisol variations showed post prandial peaks; they could be induced by oral--but not intravenous--glucose tolerance tests, and were inhibited by the concomitant administration of Sandostatin (a somatostatin analog). Adrenal CT scan identified a 2 cm unilateral adenoma with ipsilateral and contralateral atrophy. Surgical removal of the tumor cured the hypercortisolism with hypocortisolism. Comparative analysis of the tumoral and normal tissues showed that only the former responded in vitro to GIP (Gastric Inhibitory Polypeptide) and contained the specific mRNA of the GIP receptor. This case illustrates a new pathophysiological mechanism of tumorigenesis due to the aberrant expression of a seven transmembrane domain receptor in a tumoral tissue. The nature of the given receptor induced a particular clinical phenotype related to food intake.
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PMID:[Aberrant expression of the GIP (Gastric Inhibitory Polypeptide) receptor in an adrenal cortical adenoma responsible for a case of food-dependent Cushing's syndrome]. 1033 44

Ectopic ACTH secretion represent 10 to 15% in the causes of Cushing's syndrome. Carcinoid tumor of the thymus is a rare neoplasm and is currently believed to arise from population of thymic cells of neural crest origin. We present the case of a 43-year-old man with a corticotropin hormone (ACTH) secreting thymus carcinoid. 111In-octreotide scintigraphy demonstrated an intense uptaken on the lesion. The surgical specimen measured 17 x 18 x 18 cm and weighed 1. 25 kg. Postoperatively the patient was treated by chemotherapy and radiotherapy. A follow-up 111In-octreotide scintigraphy was normal. Very few scintigraphic images of these lesions have been published in the literature. Somatostatin receptor scintigraphy can be successful in the detection and follow-up of ACTH-secreting neuroendocrine tumors.
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PMID:[Gammagraphy of somatostatin receptors in an ACTH secreting thymic carcinoid]. 1035 22

The neuroregulation of growth hormone (GH) secretion and the state of the adipose tissue reserves are closely related. GH exerts lipolytic actions on the adipose tissue and low body weight enhances secretion of GH while obesity is associated with reduced levels of GH and blocked release of GH when challenged by all stimuli. The mediators of the regulation exerted by the adipose tissue on the GH/insulin-like growth factor-I axis are not fully understood, but in the last few years two relevant factors have emerged--free fatty acids (FFA) and the adipocyte-produced hormone leptin. FFA and GH integrate a classical feedback loop and a rise in FFA blocks GH secretion. This action is rapid, dose-related and exerted at the pituitary level with no evident hypothalamic participation. A pharmacological reduction in FFA enhances secretion of GH and eliminates the GH blockade of obesity and Cushing's syndrome. The discovery of leptin has expanded our knowledge of the way in which the adipose tissue participates in some neuroendocrine actions. Obesity is associated with elevated levels of serum leptin while undernutrition and fasting lead to low leptin. In fasted rats, the pattern of GH pulsatility is eliminated with a near absence of spontaneous peaks, but the administration of leptin by the intracerebroventricular (i.c.v.) route restores the altered pattern. When fed rats receive antileptin antibodies i.c.v the normal pattern is reversed to an absence of pulses, reminiscent of the fasting state. These results are the first demonstration that, at least in experimental animals, leptin is a relevant factor in GH regulation. Leptin has no direct pituitary action and its action at the hypothalamic level appears to be mediated by neuropeptide Y, being the final step in a reduction in the somatostatin tone. On the other hand, the action of GH on leptin levels seems to be tenuous in humans, but in the near future it will be possible to investigate the action of leptin on human GH. As the hypothalamic neuroregulation of GH secretion in humans is unlike that in the rat, a crucial point for elucidation will be the actions, if any, and the mechanisms by which leptin participates in GH regulation in humans, as well as its alterations in disease states.
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PMID:Regulation of growth hormone secretion by signals produced by the adipose tissue. 1044 66

Functional metastatic adrenocortical carcinoma is an uncommon cause of Cushing's syndrome, which rarely responds to conventional treatment. A patient presenting with Cushing's syndrome secondary to adrenocortical carcinoma underwent surgical resection. Postoperatively, she developed metastatic disease resistant to conventional chemotherapy. Octreotide, a somatostatin analogue which is effective in the treatment of several types of neuroendocrine tumour, was tried to ameliorate her secretory symptoms, but without any therapeutic effect.
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PMID:Lack of response to octreotide in Cushing's syndrome due to metastatic adrenocortical carcinoma. 1044 70

Initially, the distinction between "functional" and "non-functional" adenomas was a purely clinical notion. A "non-secreting" adenoma was not considered to cause acromegaly nor Cushing's syndrome nor amenorrhea-galactorrhea syndrome. The term "chromophobe adenoma" has been used since the advent Herlant tetrachrome. More recently immunocytochemistry methods have demonstrated that most of the "clinically non functional" adenomas (chromophobe with classical histology) are actually gonadotrophin secreting adenomas or gonadotroph adenomas. Due to progress in immunocytochemistry applied to operated adenomas, it is now known that gonadotroph tumors account for 15 to 20% of all pituitary adenomas. Gonadotroph adenomas are monoclonal but their pathogenesis, unlike somatotroph adenomas causing acromegaly and despite numerous molecular studies, remains unknown. Gonadotroph adenomas are most always discovered in patients presenting a pituitary syndrome (half to three-quarters consult for a visual field disorder). Pituitary imaging almost always demonstrates a macroadenoma: two-thirds of the macroadenomas are enclosed. Anterior pituitary insufficiency is much more frequent than gonad hyperstimulation whether testicular (macro-orchidia) or ovarian (ovarian hyperstimulation similar to that observed in ovulation induction). A careful analysis of hormone assay results shows that baseline concentrations of gonadotrophin or their free sub-units is elevated in 30 to 50% of cases (especially FSH in men, and the free a sub-unit in premenopausal women). Dynamic tests contribute little to diagnosis: the GnRH test is positive in 75 to 100% of cases, the TRH test in 60 to 70% for FSH (or alpha) and when there is already a baseline hypersecretion of FSH (or a) in 20 to 30% of the cases for the LH when the baseline LH concentration is high. The immunocytochemistry of gonadotroph adenomas is slightly different from that of other adenomas: generally, only 5 to 10% of the cells, grouped in islets of variable size, dispersed in the tumoral parenchyma, bind anti-FH, anti-LH and/or anti-sub-unit a antisera. Surgery is the primary treatment for gonadotroph adenomas. Complementary radiotherapy may be discussed in case of a postoperative remnant. It is probably effective against recurrence. Medical treatment (dopaminergic agonists, somatostatin analogs, GnRH agonists and antagonists) have given disappointing results.
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PMID:[Gonadotroph pituitary adenomas]. 1097 Sep 52

The stress system coordinates the adaptive response of the organism to real or perceived stressors. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine/ autonomic (LC/NE) systems and their peripheral effectors, the hypothalamic-pituitary-adrenal (HPA) axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. Thus, CRH and the LC/NE system stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the amygdala, which are responsible for the generation of fear. Hypothalamic CRH plays an important role in inhibiting gonadotropin-releasing hormone secretion during stress, while via somatostatin it also inhibits growth hormone, thyrotropin-releasing hormone and thyrotropin secretion, suppressing thus reproduction, growth and thyroid function. Glucocorticoids directly inhibit pituitary gonadotropin, growth hormone and thyrotropin secretion and make the target tissues of sex steroids and growth factors resistant to these substances. In addition, glucocorticoids stimulate hepatic gluconeogenesis, and inhibit or potentiate insulin actions on skeletal muscle and adipose tissue respectively, ultimately promoting visceral adiposity and the metabolic syndrome. Glucocorticoids also have direct effects on the bone, inhibiting osteoblastic activity and causing osteoporosis. Obese subjects with psychiatric manifestations ranging from those of melancholic depression to anxiety with perception of 'uncontrollable' stress, frequently have mild hypercortisolism, while carefully screened obese subjects with no such manifestations are eucortisolemic. The former may have stress-induced glucocorticoid-mediated visceral obesity and metabolic syndrome manifestations, which in the extreme may be called a pseudo-Cushing state that needs to be differentiated from frank Cushing syndrome. Stress-induced hypercortisolism and visceral obesity and their cardiovascular and other sequelae increase the all-cause mortality risk of affected subjects by 2-3-fold and curtail their life expectancy by several years.
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PMID:The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. 1099 9

A 31-year-old woman presented with progressive weight gain, facial acne, round facies, hirsutism, and secondary amenorrhea. Her plasma cortisol, urinary free cortisol, and plasma ACTH were elevated. CT scan of abdomen revealed bilateral diffuse adrenal enlargement. MRI of pituitary failed to identify a lesion. CT scan of chest revealed an 8 mm nodule in the lower lobe of the left lung. The diagnosis of ectopic Cushing's syndrome was made. The lung tumor was surgically removed. The tumor measured up to 1.5 cm in diameter. By light microscopy, a tumor with characteristic features of bronchial carcinoid was noted. Immunostains were positive for neuron-specific enolase, synaptophysin, chromogranin, low-molecular-weight keratin, ACTH, beta endorphin, corticotropin-releasing hormone, bombesin, alpha subunit, and somatostatin. Electron microscopy revealed an endocrine neoplasm. The secretory granules displayed great variation subdividing the endocrine neoplasm. The secretory granules displayed great variation subdividing the cell population into an undetermined number of phenotypes. In situ hybridization demonstrated positivity for pro-opiomelanocortin mRNA in the tumor cells. Postoperatively, plasma cortisol had fallen. The patient remained symptom-free one year later. The case presented here was regarded as a plurihormonal bronchial carcinoid associated with ectopic Cushing's syndrome. This unique plurihormonal bronchial carcinoid tumor produced three hormones, ACTH, CRH, and bombesin, that may have contributed to the patient's ectopic Cushing's syndrome.
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PMID:Plurihormonal Bronchial Carcinoid Associated with Ectopic Cushing's Syndrome. 1211 73

Pulmonary carcinoid tumors are neuroendocrine malignant tumors that make up 1% to 2% of all lung tumors. According to histopathologic criteria, carcinoids can be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids can be placed in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC to intermediate AC to high-grade large-cell neuroendocrine carcinoma and small-cell lung carcinoma. Familial pulmonary carcinoids are rare. The most common symptoms are hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and chest pain, unilateral wheezing, and shortness of breath. Paraneoplastic syndromes are rare and include carcinoid syndrome, Cushing's syndrome, and ectopic growth hormone-releasing hormone secretion. The diagnosis is usually established by flexible bronchoscopy and biopsy, although occasionally this can result in severe hemorrhage. Immunoscintigraphy by somatostatin analogs can also be useful in diagnosis. The treatment of choice is surgical resection, and prognosis is relatively good in TC, although it is worse in AC. The role of radiotherapy and chemotherapy as part of multimodality treatment or palliation is still debated.
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PMID:Update in pulmonary carcinoid tumors: a review article. 1283 56

Cushing's syndrome (CS) due to ectopic ACTH secretion (EAS) has a high morbidity and mortality, because of the underlying tumor and the sequelae of severe hypercortisolemia. Therefore, rapid treatment of ectopic CS is mandatory. Scintigraphy shows that up to 80% of ectopic ACTH-producing tumors have somatostatin receptors. While this suggests that somatostatin analogs may reduce ACTH production and treat patients with EAS, the therapeutic role of these agents is still evolving. Here we demonstrate the spectrum of responses to octreotide therapy in 3 patients with EAS. Diagnostic imaging with the 111In-pentetreotide scan did not predict the therapeutic response to octreotide. Two patients with positive somatostatin receptor scintigraphy failed to respond to octreotide, while one with a negative scan reached eucortisolemia on a maintenance dose of 75 microg octreotide twice daily or octreotide LAR 30 mg per month. We conclude that octreotide is not a first line agent to control hypercortisolemia but may be a useful agent when other inhibitors of steroidogenesis fail or parenteral administration is required. Before therapy an octreotide challenge test may predict therapeutic response. Cortisol levels should be monitored regularly on somatostatin analog therapy, because of its unpredictable long-term pharmacodynamic profile.
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PMID:Is there a therapeutic role for octreotide in patients with ectopic Cushing's syndrome? 1466 23

Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal gland. Most are caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Alternatively, the glucocorticoid excess may be due to adrenal neoplasia or to ectopic ACTH-secreting tumors. Cushing's syndrome is characterized by endocrine and metabolic alterations such as truncal obesity, hypertension, weakness, amenorrhea, hyperglycemia, osteoporosis and depression. Unless treated, the disease is associated with high morbidity, and ultimately, mortality. Depending on the etiology of Cushing's syndrome two different treatment modalities are possible: reduction of pituitary ACTH production or reduction of adrenocortical cortisol secretion. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the primary treatment of choice for the reduction of ACTH secretion. In the last years there was much progress in understanding the molecular mechanisms that control the function of the hypothalamic-pituitary-adrenal axis. Thus, new insights made it possible to identify potential drug targets for the treatment of Cushing's syndrome. The present article reviews different drug targets and therapeutic options including drugs that control the central ACTH regulation, e.g. by modulating signaling pathways and transcriptional regulation of ACTH biosynthesis, corticotrophin releasing hormone (CRH) or glucocorticoid receptor antagonists, inhibitors of glucocorticoid synthesis, ketoconazole, somatostatin and dopamine analogs. Some of these substances might be useful for the treatment of Cushing's syndrome.
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PMID:New perspectives in the treatment of Cushing's syndrome. 1557 85


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