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)

How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin's inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17beta orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 microg/1.73 m(2).h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 microg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10(-4) interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 +/- 6.1% (mean +/- SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 +/- 1 to 245 +/- 35 pg/mL [42 +/- 4 to 920 +/- 110 pmol/L] (P < 10(-4)); decreased serum concentrations of LH (P = 0.018), FSH (P < 10(-4)), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 +/- 0.07 to 0.87 +/- 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin's maximal suppression of GH by 89 +/- 4.7% (P < 10(-4) below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38-0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2-7.0) (estradiol) microg/1.73 m(2)/h (P < 10(-4)), denoting muting of somatostatin's inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10(-4)). The foregoing effects were specific, because estrogen did not alter somatostatin's dose-dependent enhancement (P < 10(-4)) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic. In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin's dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin's reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.
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PMID:Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion. 1144 79

In rodents leptin inhibits food intake, stimulates energy expenditure, reverses obesity, ameliorates insulin resistance, and accelerates sexual maturation. These potent and diverse effects have stimulated interest in exploring a role for leptin in the treatment of human metabolic disorders. However, the significance of leptin in human (patho)physiology is still being investigated. The present review summarizes current knowledge of leptin regulation, provides a critical assessment of initial experience with leptin therapy, and discusses potential targets for recombinant leptin therapy in humans. The results of numerous studies indicate that leptin is indeed a regulated human hormone: The physiological factors that influence leptin secretion include gender, adiposity, physical exercise, feeding, and caloric restriction. Several hormones, including insulin, glucocorticoids, estradiol, growth hormone, testosterone, somatostatin, and insulin-like growth factor-I also modulate leptin secretion. The results of initial trials of leptin therapy in humans have become available. Treatment with recombinant human leptin (0.028 mg/kg) induced a progressive weight loss (without evidence of tachyphylaxis) in a morbidly obese patient with congenital leptin deficiency. The weight loss averaged 1-2 kg/month, was associated with preservation of lean muscle mass, and was almost exclusively accounted for by depletion of body fat. Administration ofrecombinant leptin (0.01-0.3 mg/kg) also resultedin a dose-dependentweight loss among lean and obese humans with presumably normal leptin genotype. Thus leptin may have a therapeutic role in humans, but its physiological functions and regulation first need to be fully unravelled.
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PMID:Human leptin regulation and promise in pharmacotherapy. 1146 18

Two fundamentally different methods are currently used for the determination of free insulin-like growth factor-I (IGF-I): ultrafiltration by centrifugation (UF) and direct immunoradiometric assay (IRMA). The aim was to evaluate a commercial IRMA (DSL, Webster, TX, USA) and to compare it with UF. In the IRMA it is recommended that samples be incubated for 2 h at 5;C. When comparing samples (n = 8) incubated for 1 and 2 h, levels increased by 27 +/- 5% (P< 0.0001). When incubating samples at 22;C instead of 5;C, levels increased by 192 +/- 32% (P< 0.0001). Addition of IGF-binding protein-1 (IGFBP-1) to normal sera (n = 6) dose-dependently decreased ultrafiltered free IGF-I only (P< 0.0007). Similarly, UF was more sensitive than IRMA to addition of IGFBP-2 (P< 0.05). In healthy subjects (n = 35) IRMA yielded 20% higher levels than UF (1.09 +/- 0.09 vs 0.91 +/- 0.12 microg/L; P< 0.0001). IRMA and UF yielded similar results in healthy subjects treated with IGF-I (n = 5) or growth hormone (n = 7) and in acromegalic patients (n = 6) before and after somatostatin analogue treatment. However, marked differences were observed in conditions with elevated IGFBP-1 and -2. In type-1 diabetics (n = 23) ultrafiltered free IGF-I was more reduced than IRMA free IGF-I (38 +/- 9 vs 76 +/- 7% of matched controls (n = 13); P< 0.0001). In patients with chronic renal failure (n = 25), IRMA free IGF-I was identical to control levels (n = 13), whereas ultrafiltered free IGF-I was decreased by 51 +/- 7% (P< 0.0001). Similarly, women with anorexia nervosa (n = 9) studied before and after weight gain showed significant changes in ultrafiltered free IGF-I only (P< 0.03). In conclusion, IRMA was not very robust with respect to variations in sample incubation and this may bias results. IRMA generally yielded higher levels than UF, in accordance with the knowledge that IRMA measures free plus readily dissociable IGF-I. IRMA was less affected than UF by added IGFBP-1 and -2, and reductions in free IGF-I were better revealed by UF than IRMA.
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PMID:Determination of free insulin-like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay. 1147 78

Conventional treatments for acromegaly include surgery, radiotherapy, dopamine agonists and somatostatin (SMS) analogues, which effect disease control by lowering circulating growth hormone (GH). Due to variability in tumour characteristics, combinations of these treatment modalities leave a significant number of patients with sub-optimal serum GH and insulin-like growth factor-I (IGF-I) levels, which have been linked to increased morbidity and mortality. The GH receptor antagonist pegvisomant is a genetically engineered analogue of GH that prevents functional dimerisation of the growth hormone receptor (GHR); a process that is critical to GH action at the cellular level. A crucial amino acid substitution at Gly(120) to Arg(120) within the third alpha helix of the antagonist prevents functional GHR dimerisation. Pegvisomant represents a novel treatment for acromegaly as, unlike existing treatment modalities, the effectiveness of pegvisomant is independent of pituitary tumour characteristics. Initial clinical studies in patients with active acromegaly have demonstrated serum IGF-I normalisation in over 90% of patients receiving 20 mg per day, such that, in terms of serum IGF-I normalisation, pegvisomant now represents the most effective medical treatment for acromegaly. Although there are limited long-term data on the use of pegvisomant and questions regarding pituitary tumour growth and altered liver function remain, this therapy offers the prospect of serum IGF-I normalisation in the vast majority of patients with active acromegaly.
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PMID:The place of pegvisomant in the management of acromegaly. 1177 81

Vasoactive intestinal peptide (VIP) stimulates the proliferation and invasiveness of malignant prostatic cells. Receptors for VIP and the closely related growth hormone-releasing hormone (GH-RH) show considerable homology and are found in prostatic and other carcinomas. Among various analogs of GH-RH synthesized, JV-1-52 is a non-selective VIP/GH-RH antagonist, whereas JV-1-53 is a VIP antagonist devoid of GH-RH antagonistic effect. In our study, nude mice bearing PC-3 human androgen-independent prostate carcinomas were treated with JV-1-52 or JV-1-53 (20 microg/day, s.c.) for 28 days. Both antagonists produced a similar reduction in tumor volume (62-67%, p < 0.01) and tumor weight (59-62%; p < 0.05) vs. controls and extended tumor doubling-time from 9.1 to about 16 days (p < 0.05). To investigate the mechanisms involved, in another study we compared the effects of JV-1-53 with those of somatostatin analog RC-160. VIP antagonist JV-1-53 reduced tumor weight by 67% (p < 0.01) and suppressed the expression of mRNA for c-fos and c-jun oncogenes by about 34% (p < 0.05), without affecting serum levels of insulin-like growth factor-I (IGF-I). In contrast, RC-160 (50 microg/day) reduced serum IGF-I by 19% (p < 0.05), but did not significantly decrease tumor weight. mRNA for VIP and high affinity receptors for VIP were detected on PC-3 tumors. Our results suggest that VIP/GH-RH antagonists can inhibit the growth of androgen-independent prostate cancer by abrogating the autocrine/paracrine mitogenic stimuli of VIP. The ability of GH-RH antagonists to block tumoral VIP receptors, in addition to GH-RH receptors, could be potentially beneficial for prostate cancer therapy.
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PMID:Inhibition of PC-3 human prostate cancers by analogs of growth hormone-releasing hormone (GH-RH) endowed with vasoactive intestinal peptide (VIP) antagonistic activity. 1192 Jun 25

Growth in humans is a complex process, controlled at numerous levels and by a myriad of factors. These factors may act centrally or peripherally and may be hormones, receptors, or transcription factors. Many of these probably are still unknown. The factors that are discussed here include those that act on the developing pituitary gland (transcription factors including LHX3, HESX1, PROP1, and PIT-1); those that regulate the normal activity of the pituitary (hypothalamic hormones such as GHRH, Ghrelin [growth hormone secretagoguel and somatostatin); those factors coming from the pituitary (essentially growth hormone [GH]); and the downstream modulators, transducers, and effectors of GH (including the GH receptor/GH binding protein, insulin-like growth factor-I and -II, their receptors, and their binding factors). What is becoming increasingly clear is the role of genetics in determining stature. This review discusses the most clinically relevant factors, with an emphasis on ontogeny, genetic inheritance, and clinical presentation.
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PMID:Genetic disorders of human growth. 1209 84

Acromegaly is a chronic disorder invariably caused by a growth hormone (GH)-secreting pituitary tumour and is characterised by disabling symptoms (sweating, arthralgia, headache, paraesthesiae, fatigue), significant comorbidities (diabetes mellitus, hypertension, sleep apnoea), and premature mortality. Symptomatic control can be achieved by lowering insulin-like growth factor-I (IGF-I) concentrations to within the age-adjusted normal range, and survival can be improved to match that of the general population. However, even with optimal surgery and current medical therapies (dopamine agonists, somatostatin analogues), 30% to 50% of patients do not achieve target concentrations of IGF-I and GH. Pegvisomant is a new GH-receptor antagonist that blocks GH activity by inhibiting functional dimerisation of GH-receptors. Given as subcutaneous injections at dosages of 10 mg, 15 mg, or 20 mg/day for 3 Months, pegvisomant normalised serum IGF-I concentrations in, respectively, 54%, 81%, and 89% of acromegalic patients. Moreover, long-term pegvisomant therapy normalised IGF-I concentrations in 97% of patients treated for 12 Months or longer, with no evidence of tachyphylaxis. Pegvisomant is the most effective medical therapy, reported to date, in terms of normalisation of circulating IGF-I concentrations. In addition, pegvisomant appears to be safe and well tolerated. Although additional long-term studies are required to further assess safety, the introduction of this innovative treatment should allow for optimal disease control in patients with acromegaly.
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PMID:Pegvisomant: an advance in clinical efficacy in acromegaly. 1267 Feb 98

The primary treatment of acromegaly remains transsphenoidal adenomectomy, yet the tissue overgrowth of acromegaly often progresses following surgery, and responds to radiotherapy only after significant delay. Persistently elevated serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations can be normalized in about half of post-surgery acromegalics using the pharmacologic alternatives presently available, the dopamine agonists (DA) and somatostatin (SST) analogs. Cabergoline, the most efficacious DA, normalizes IGF-I in approximately 37% of patients, whereas the long-acting SST analogs, Octreotide LAR and Lanreotide SR, do so in 66%. Significant tumor shrinkage may be attained with SST analogs in particular, and when necessary, the primary medical treatment of acromegaly may be successfully addressed with this class of drugs. Greatly enhanced efficacy is expected from the GH receptor antagonist pegvisomant, which is nearing market availability and will enable the normalization of serum IGF-I in virtually all patients treated. We review here the pharmacologic treatments of excessive GH secretion.
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PMID:Medical management of growth hormone-secreting pituitary adenomas. 1267 3

Somatostatin analogues are potent growth hormone and glucagon inhibitors and are commonly used in the treatment of several endocrine and non-endocrine disorders. We report severe and longstanding hypoglycemia triggered by long-acting octreotide (Sandostatin LAR) in a 62-year-old women with malignant mesenchymal tumor. Hypoglycemia developed after 6 hours of octreotide injection and she was admitted to the emergency unit with sweating, tremor, palpitation and confusion. On admission, her plasma glucose level was: 17 mg/dl (normal: 65-110), cortisol: 31 microg/dl (normal: 5-25), insulin: 4.32 microIU/ml (normal: 6-27), C-peptide: 2.64 ng/ml (normal: 0.9-4.0), growth hormone: 0.06 ng/ml (normal: 0.06-5.0), insulin-like growth factor-I: 8.5 ng/ml (normal: 101-303), insulin-like growth factor binding protein-3: 1715 ng/ml (normal: 2020-3990). Intravenous dextrose infusion was given for a month to sustain normoglycemia since hypoglycemia recurred following cessation of infusion. Therefore, prednisolone, 35 mg/day was added and the parenteral dextrose infusion rate was decreased gradually and finally stopped. Normoglycemia could be maintained with prednisolone 20 mg/day. In patients prone to tumor hypoglycemia, long-acting octreotide may trigger severe and prolonged hypoglycemia due to suppression of counter-regulatory hormones; clinical trial with short-acting octreotide may be warranted to predict and prevent this life-threating complication.
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PMID:Severe and prolonged hypoglycemia triggered by long-acting octreotide in a patient with malignant mesenchymal tumor: case report. 1267 21

Acromegaly is a rare disabling disorder that results in premature death. The excess mortality and morbidity are the result of prolonged elevation of growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, and vigorous control of these improves well-being and restores life expectancy to normal. Recognition of the benefits of treatment has emphasised the need for optimal control of the GH/IGF-I axis. Transsphenoidal surgery is first-line therapy in the majority of patients; however, as most tumours are macroadenomas, cure rates are low. The role of radiotherapy is evolving and, although extremely effective at controlling tumour growth, it can take up to 15 years to control GH & IGF-I levels. In the interim, medical therapy is necessary. Dopamine agonists are inexpensive oral agents but, although most patients experience some benefit, GH and IGF-I levels are only normalised in around 35-40% of patients, and side effects are common. Somatostatin analogues are the gold standard of medical treatment. They can induce tumour shrinkage in a proportion of patients and can normalise the GH/IGF-I axis (at best) in approximately 65% of individuals; however, this leaves a significant cohort uncontrolled. The advent of the GH receptor antagonist pegvisomant provides the potential for IGF-I to be normalised in virtually every patient, but this novel form of therapy, which does not act on the pituitary, also raises many questions.
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PMID:Medical treatment in acromegaly. 1464 22


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