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)

In normal subjects, the major form of circulating IGF is the GH-dependent 150 K complex. As demonstrated by gel-permeation chromatography, the acid-labile subunit (ALS) purified from human serum, incubated for 2 h at 20 degrees C with [125I]IGF-I and rIGFBP-3, is able to increase not only the molecular weight (mol. wt.) of the IGF-IGFBP-3 complex, but also the amount of IGF-I bound. In both charcoal and polyethylene glycol ligand binding assays, competitive binding curves for the displacement of [125I]IGF-I from rIGFBP-3 by increasing concentrations of unlabeled IGF-I showed an increased binding activity of rIGFBP-3 in the presence of ALS. The effect of ALS on rIGFBP-3 binding activity was dose dependent. In addition, ligand and immunoblot revealed that ALS and rIGFBP-3 are able to form a high mol. wt. complex in the absence of IGF peptide. On the basis of these data, ALS seems to have a more complex function than that of simply increasing the mol. wt of the IGF-IGFBP-3 complex. The regulation of ALS synthesis by rat hepatocytes in primary culture has also been evaluated by immunoblot. In agreement with the in vivo finding of an inhibitory effect of octreotide (a somatostatin analog) on the formation of the 150 K complex in acromegalic subjects, we could observe in vitro that octreotide produces a dose-dependent inhibition of ALS secretion into the hepatocyte conditioned medium. TGF-beta 1 was also inhibitory at high doses. On the contrary, we could not evidence any effect of IGF-I or IGF-II, while a small increase has been noted after incubation with T3.
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PMID:Functions and regulation of the acid-labile subunit of the 150 K complex. 881 66

Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This may be the consequence of age-related cholinergic impairment, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impairment, we verified the GH response to GHRH (1 microgram/kg i.v. at 0 min) alone or combined with pyridostigmine (PD), a cholinesterase inhibitor (60 and 120 mg, respectively, in children and adults, orally at -60 min) in 15 DS children (13.5 +/- 0.6 years) and in 11 DS young adults (24.0 +/- 1.2 years). Fifteen normal children (11.9 +/- 0.5 years), 15 normal adults (27.3 +/- 0.9 years) and 16 normal elderly (76.3 +/- 1.5 years) were studied as controls. IGF-I levels showed an age-related reduction both in DS (children vs. adults, mean +/- SEM:354.8 +/- 44.9 vs. 204.4 +/- 29.4 micrograms/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly:281.4 +/- 36.3 vs. 175.4 +/- 11.2 vs. 72.5 +/- 6.6 micrograms/l, p < 0.001). The GH response to GHRH in DS children was higher than in DS adults (areas under curve: 1,197.6 +/- 241.5 vs. 434.4 +/- 83.3 micrograms/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 +/- 128.4 vs. 800.8 +/- 124.5 micrograms/l/h) and both were higher than that in elderly subjects (296.0 +/- 61.0 micrograms/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children (1,068.1 +/- 145.7 vs. 1,897.4 +/- 198.8 micrograms/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 +/- 144.7 vs. 2,172.1 +/- 156.1 and 2,347.6 +/- 322.4 micrograms/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) than that in normal adults and similar to that in normal elderly subjects. In conclusion, the present data demonstrate that the stimulated GH secretion in DS undergoes an accelerated age-related reduction. They also suggest the existence of a precocious impairment of central cholinergic activity in DS, which, in turn, could cause somatostatinergic hyperactivity and reduced GH secretion.
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PMID:The enhancing effect of pyridostigmine on the GH response to GHRH undergoes an accelerated age-related reduction in Down syndrome. 887 21

Octreotide nasal powder is a delivery system of the somatostatin analogue developed to overcome the inconvenience of repeated subcutaneous administrations. Eight patients with clinically active acromegaly were treated for three months with octreotide nasal powder which was administered at the initial dosage of 0.125 mg tid, doubling the dosage up to 2 mg tid in order to obtain a mean GH value below 5 micrograms/l during 8 daytime hours. In 4 of these patients, treatment was prolonged till the sixth month. Blood samples were taken on days 15, 29, 43, 55, 90, 120, 150, 180 for GH, IGF-I, IGFBP-3, IGFBP-1 and insulin measurements. Before treatment, mean daytime GH and morning IGF-I serum levels were both increased but not correlated with each other. Serum IGFBP-3 levels were higher than normal and positively correlated with those of GH, IGF-I and insulin. Insulin levels were elevated and positively correlated with those of GH but not with those of IGF-I and IGFBP-1. Serum IGFBP-1 levels were in the low normal range and not correlated with any of the other parameters. Treatment with octreotide nasal powder induced in all patients a marked decrease of GH which lowered below 5 micrograms/l in 7/8 patients and IGF-I levels, which fell within the normal range in 1 patient. Serum IGFBP-3 and insulin concentrations decreased by 26% and 71%, respectively, and those of IGFBP-1 underwent an only transient increase in 5/8 patients. Opposite changes of insulin and IGFBP-1 levels, with a decrease of the former followed by an increase of the latter were noted during the 8 hours following an octreotide nasal insufflation. During chronic octreotide treatment, positive correlations were found between GH and IGF-I, GH and IGFBP-3, IGF-I and IGFBP-3, insulin and IGFBP-3 and insulin and IGF-I. An improvement of the clinical picture was registered in all patients after a few days of octreotide nasal powder administration. Treatment was well tolerated, with only mild side effects and no significant changes in the nasal mucosa, and the patients' compliance was excellent.
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PMID:Effect of chronic treatment with octreotide nasal powder on serum levels of growth hormone, insulin-like growth factor I, insulin-like growth factor binding proteins 1 and 3 in acromegalic patients. 890 79

Initial diabetic renal hypertrophy is preceded by a transient increase in kidney insulin-like growth factor I(IGF-I). In the present study streptozotocin-diabetic rats were treated with a new somatostatin analogue (lanreotide), insulin or placebo for 7 days and compared to non-diabetic control rats. Kidney IGF-I changes were examined in the renal cortex, medulla, and whole kidney homogenates. The renal cortex contained approximately 5.5 times more IGF-I than the renal medulla (p < 0.01); further, IGF-I increased transiently and more pronouncedly in the renal cortex compared to the medulla. Lanreotide treatment significantly inhibited diabetic renal and glomerular growth compared to placebo-treated diabetic rats. Further, lanreotide treatment was followed by a significantly lower medulla IGF-I by day 2, while lanreotide had no effect on cortex IGF-I accumulation. In conclusion, IGF-I accumulated transiently and was more pronounced in the real cortex compared to the renal medulla and, further, lanreotide prevented diabetic renal and glomerular growth bringing new evidence that intervention with somatostatin analogues may have a role in the prevention of experimental diabetic kidney disease.
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PMID:Effect of lanreotide on local kidney IGF-I and renal growth in experimental diabetes in the rat. 893 85

To determine if the mode of 17 beta-estradiol (E2) administration affects growth hormone (GH) concentrations, eight postmenopausal women were studied under the following conditions: (1) control (no E2), (2) oral E2 (Estrace, 1 mg every 12 h for 2 weeks) and (3) transdermal E2 (Estraderm patch, 0.1 mg, two patches changed daily for 2 weeks). Blood was collected every 5 min for 24 h and assayed for serum GH concentrations using a sensitive chemiluminescence assay. Serum E2 levels were comparable during both E2 treatment regimens when measured with a specific chemiluminescence assay. The 24-h integrated GH concentrations (IGHC, min . micrograms/L) increased in all eight subjects from (mean +/- SE) 494 +/- 102 during control to 860 +/- 111 (P < 0.05) and 832 +/- 149 (P < 0.05) during oral and transdermal E2, respectively. Both E2 treatments significantly increased GH pulse height, individual pulse area, incremental pulse amplitude, interpeak valley concentration, and interpeak valley nadir (as measured by Cluster algorithm) when compared with control. No significant differences were observed in the number of GH pulses per 24 h. Insulin-like growth factor-I (IGF-I, micrograms/L) concentrations decreased from 165 +/- 19 (control) to 109 +/- 11 (oral E2, P < 0.05) and 122 +/- 15 (transdermal E2, P < 0.05). No statistically significant differences in attributes of pulsatile GH release or IGF-I concentrations were observed between the oral and transdermal E2 treatments. We conclude that both oral and transdermal E2 treatment increase serum GH concentrations in postmenopausal women. This increase is manifested by larger GH pulses and higher basal (interpulse) GH levels, not by changes in pulse frequency. Both routes of E2 administration decrease serum IGF-I concentrations, which may attenuate IGF-I negative feedback on pituitary somatotrophs and hypothalamic somatostatin secretion, resulting in enhanced pulsatile GH release.
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PMID:Both oral and transdermal estrogen increase growth hormone release in postmenopausal women--a clinical research center study. 896 60

Medical therapy is frequently needed to normalize growth hormone/insulin-like growth factor I secretion in acromegaly. The aim of this study was to determine the long-term effects of the slow-release (SR) somatostatin analogue lanreotide in 57 acromegalic patients. SR lanreotide (30 mg) was given every 14 days for 12 months. In 33% of patients, the drug dosage was raised to 60 mg and/or the time interval was shortened to 10 days. Two months of clinical evaluation followed drug discontinuation in 47 out of 48 (84%) patients who completed the 12-month period. A drug-related decrease in GH/IGF-I levels was observed. Basal GH/IGF-I levels were significantly (P < 0.001) reduced at 12 months, IGF-I was normalized in 35% of patients and GH levels were < 5 micrograms L-1 in 54%. There was a clinical improvement in patients complaining of joint pain, rachialgias, headache, digital paraesthesias and hyperhidrosis. Soft-tissue changes were documented by significant (P < 0.001) decreases in finger size. In 52 (91%) patients without overt diabetes, a slight but significant increase in integrated glycaemia (P < 0.001) was noted, while integrated insulin levels were reduced (P < 0.001). Of 33 (58%) patients with normal basal ultrasound examination of the gall bladder, three (9%) had developed asymptomatic gall stones or biliary sludge after 12 months. Adverse events were generally mild. They frequently (52%) occurred after the first SR lanreotide administration; only 28% were recurrent and 20% appeared for the first time during therapy. SR lanreotide is an effective treatment in most unselected acromegalic patients. Tolerance towards the drug is high. Subjective benefits seem to override the simple biochemical control of the disease. Glucose homeostasis more than the incidence of gall stones seems to require monitoring on therapy. SR lanreotide is clearly advantageous in improving patient compliance with medical treatment for acromegaly.
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PMID:Clinical results of long-term slow-release lanreotide treatment of acromegaly. 913 75

The value of somatostatin receptor scintigraphy (SRS) to predict the effect of somatostatin analog therapy on pituitary adenomas is not clear, due to the use of different radiopharmaceuticals (123I-Tyr3-octreotide and 111In-pentetreotide) and the small number of patients in previous studies. We used 111In-pentetreotide scintigraphy in 49 patients in order to (i) correlate SRS results with basal tumor volume as well as volume- and hormone-response to 3 months of octreotide therapy (Oct-Tx). (ii) identify tumor remnants after incomplete surgery and (iii) evaluate any correlation with immuno histology. Twenty-five patients had a GH-secreting adenoma (GH-A, 15 prior to intended surgery, 10 with persistent/recurrent disease after previous therapy). Twenty-four patients had a clinically non-functioning adenoma (NF-A). For SRS, planar and single photon emission computer tomographic images (SPECT) were recorded 4 h and 24 h post injection. SRS grading was as follows: GO, no uptake: G1, uptake comparable to normal pituitary; G2, increased uptake: G3, very intense uptake. G2/3 was seen in 8/25 GH-A and in 12/24 NF-A. Pretreatment tumor volume (magnetic resonance imaging (MRI) tended to be related to 111In-pentetreotide uptake in GH-A with a tumor visible on MRI (G0/1 (n = 10) vs G2/3 (n = 8): 3.6 +/- 1.9 vs 10.5 +/- 6.5 cm3 (mean +/- S.E.), P = 0.051), but not in NF-A (G0/1 (n = 12) vs G2/3 (n = 12): 17.0 +/- 10.1 vs 14.3 +/- 3.6 cm3). SRS did not identify a tumor remnant in the 7 MRI-negative patients with persistent post-operative acromegaly. Basal GH (6-h profile) and IGF-1 in GH-A did not correlate with SRS results (G0/1 (n = 17) vs G2/3 (n = 8), GH: 32.3 +/- 18.2 vs 29.3 +/- 7.4 micrograms/l IGF-I: 851 +/- 80 vs 1038 +/- 153 micrograms/l). During Oct-Tx of GH-A neither tumor shrinkage nor GH suppression was related to SRS results. In 6 NF-A classified as gonadotropinomas (by their plasma glycoprotein hormone or alpha-subunit concentrations, basally and/or in response to TRH) 111In-pentetreotide uptake was not different from that of the non-gonadotropin/non-secreting adenomas. SRS results were not related to the immunohistological subtype in 22 GH-A (monohormonal mixed somatotrope/lactotrope, plurihormonal) or in 22 NF-A (null-cell adenomas, gonadotropinomas silent hormonal adenomas). We conclude that 111In-pentetreotide SRS reflects tumor volume poorly in GH-A and not at all in NF-A. It does not predict the effect of Oct-Tx on the volume of both GH-A and NF-A, nor on the GH concentration in GH-A. 111In-pentetreotide SRS is unable to identify post-operative tumor remnants not visible on MRI.
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PMID:Results of somatostatin receptor scintigraphy do not predict pituitary tumor volume- and hormone-response to ocreotide therapy and do not correlate with tumor histology. 915 Jun 92

It has been surmised that GH exerts feedback action on the hypothalamus and thereby regulates its own secretion. Our previous studies suggested that GH acts on somatostatin neurons in the hypothalamic periventricular nucleus (PeV) and neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC). However, there remains uncertainty whether GH acts directly or indirectly through the generation of IGFs on the hypothalamus to regulate its own secretion. To examine this, rat GH (rGH) or human IGF-I was injected directly into a defined area of the hypothalamus, and the blood GH profile was observed in conscious male rats. In the rats given 0.5 microgram rGH into the ARC or PeV bilaterally, GH secretion was inhibited, and the inhibition lasted for 12 h. During the period of inhibition, the duration and amplitude of GH pulses were significantly decreased and the episodic secretion of GH appeared irregularly compared with the vehicle-injected control rats. In control rats given the vehicle or those given rGH into the lateral hypothalamus, the blood GH profile did not change and pulsatile GH secretion was produced every 3 h. When 0.1 microgram IGF-I was injected into the ARC or PeV bilaterally, the blood GH secretory pattern was not affected. Together with the results of our previous studies showing that c-fos gene expression was induced by systemic administration of GH and that GH receptor mRNA was contained in somatostatin neurons in the PeV and NPY neurons in the ARC, the data of the present study indicate that GH, but not IGF-I, acts on the cells in the ARC and the PeV or in their vicinity to inhibit its own secretion, presumably by activating the somatostatin and NPY neurons.
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PMID:Microinjection of rat GH but not human IGF-I into a defined area of the hypothalamus inhibits endogenous GH secretion in rats. 916 18

It is generally accepted that growth hormone influences its own secretion by modulating the activity of GHRH and SRIF neurons. To investigate if GH feedback mechanisms are already operating in the early postnatal life of the rat, we have studied in 10-day-old pups the effects of rhGH and rhIGF-I administration on GHRH and somatostatin mRNA levels. The same experiment was also performed in pups passively immunized with an anti-GHRH antiserum from the day of birth. The latter animal model had been previously characterized for presenting reduced levels of circulating GH and IGF-I. In control pups, neither rhGH (250 micrograms/kg, b.i.d., sc) nor rhIGF-I (150 micrograms/kg, b.i.d., sc) administration induced significant changes of GHRH and SRIF gene expression. The passive immunization against GHRH induced per se a trend toward an increase and a reduction of GHRH and SRIF mRNA levels, respectively. Also in these rats the treatment for 3 days with rhGH and rhIGF-I did not further modify the GHRH and SRIF mRNA levels. Based on these results, we conclude that in the 10-day-old rat GH feedback mechanisms are poorly operative, though a direct ultra-short loop mechanism involving the GHRH and SRIF systems seems already operating.
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PMID:Effects of GH and IGF-I administration on GHRH and somatostatin mRNA levels: II. A study in the infant rat. 918 22

Growth hormone (GH) secretion is pulsatile and is tightly regulated. In this chapter the effects of aging, nutrition, the feedback effects of IGF-I, and the role of body composition in the decline of GH secretion will be discussed. In GH-deficient adults there is an increase in the amount of intra-abdominal (visceral) fat. Similarly, with increasing age, there is an increase in visceral fat and there is a tight correlation between 24-hour GH release and visceral fat in the elderly. This may have serious metabolic consequences, including insulin resistance and increased cardiovascular risk. There are at least four potential mechanisms for the age-related decline in GH secretion: 1) decreased release of growth hormone releasing-hormone (GHRH); 2) increased release of somatostatin; 3) enhanced sensitivity to IGF-I feedback; and 4) decreased somatotroph mass. The latter two potential mechanisms are discussed. There is little evidence that there is any change in sensitivity to IGF-I feedback with aging and the somatotroph cell mass appears to be preserved in older subjects. The GH axis may be stimulated by either GHRH or by growth hormone-releasing peptide (GHRP) and related compounds. Chronic therapy with GHRH in GH-deficient children restores GH secretion and accelerates linear growth. Mutations of the GHRH receptor lead to GH deficiency and short stature. This indicates the essential role of GHRH in regulation of GH secretion. Growth hormone releasing peptide was discovered in 1981. Recently, the GHRP/GH secretagogue receptor has been cloned and orally active GHRP mimetics have been developed. One such compound, MK-677, stimulates pulsatile GH secretion and its effects persist for 24 hours. Oral administration of MK-677 for a month in the elderly demonstrates that this route stimulates a physiologic pattern of GH secretion. The amplitude of the GH pulses was increased but the number of GH pulses was unchanged. Thus, in older individuals, the amount of GH secreted in 24 hours is restored toward that seen in young adults. This compound also enhances GH secretion in GH-deficient adults who had been GH-deficient during childhood. The development of stable, orally active molecules to stimulate the GHRP/GH secretagogue receptor is a practical reality. These GH secretagogues may have a therapeutic role in short stature and adult GH deficiency. In addition, the use of GH secretagogues in normal aging merits investigation, as growth hormone may regulate body composition in older adults.
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PMID:Growth hormone-releasing hormone and growth hormone-releasing peptide as therapeutic agents to enhance growth hormone secretion in disease and aging. 923 54


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