bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and biochemical response following withdrawal of a long‐acting, depot injection form of octreotide (Sandostatin‐LAR®)
Authors: Stewart Paul M. , Stewart Susan E. , Clark Penny M. S. , Sheppard Michael C. 
Published: March 2003

OBJECTIVEMonthly injections of Sandostatin‐LAR® have been shown to be an effective therapy for patients with acromegaly. Because of an ongoing need to assess a patients response to definitive therapy such as surgery and/or radiotherapy, we aimed to evaluate GH levels and acromegaly symptom scores in patients withdrawing from Sandostatin‐LAR®.DESIGN AND PATIENTS12 patients with acromegaly previously treated with Sandostatin‐LAR®, 20–40 mg intramuscularly every 28 (n = 9) or 42 (n = 3) days for 12–36 months were studied at monthly intervals for 4 months following the withdrawal of the drug.MEASUREMENTSHourly fasting serum GH measurements between 0800 h and 1200 h, serum IGF‐1 and symptom scores were undertaken at 4,8,12 and 16 weeks following the last injection of Sandostatin‐LAR®. MRI/CT scans of the pituitary were undertaken at 16 weeks and compared to scans taken on Sandostatin‐LAR® within the previous 10 months.RESULTSSerum GH rose progressively from 7.7 (1.5 to 14.6) (median (range)) mIU/l at 4 weeks to 9.9 (1.5–21.8), to 12.6 (4.9–31.9) (P < 0.05 vs 4 weeks) and to 13.1 (6.0–39.1) mIU/l (P < 0.002) at 8, 12 and 16 weeks, respectively, following cessation of Sandostatin‐LAR®. IGF‐1 rose from 38.5 (12.6–73.8) nmol/l at 4 weeks to 62.4 (37.4–159) at 16 weeks (P < 0.002) and mean symptom score (comprising headache, sweating, arthralgia, paraesthesiae, tiredness) from 4.0 (0 to 10) (4 weeks) to 4.5 (0–9) (8 weeks) to 6.0 (2–10) (12 weeks) to 6.5 (4–12) (16 weeks, P < 0.05). Individual GH profiles indicated a rise in GH in 5/12 patients between weeks 4–8 and between weeks 8–12 in a further 5/12 patients. There were no changes in pituitary tumour size following discontinuation of Sandostatin‐LAR®.CONCLUSIONSGH and symptom scores rise progressively following discontinuation of Sandostatin‐LAR® in acromegalic patients. However, GH and symptom scores remain suppressed in some patients for at least 8 weeks following cessation of Sandostatin‐LAR®. We suggest that a withdrawal period of 3 months from Sandostatin‐LAR® is required in order to perform a meaningful re‐assessment of GH and clinical status.
Prevalence of Ras mutations in thyroid neoplasia
Authors: Esapa Christopher T. , Johnson Sarah J. , Kendall‐Taylor Pat , Lennard Tom W. J. , Harris Philip E. 
Published: March 2003

OBJECTIVEMutations at codons 12, 13 or 61 of ras which result in constitutive activation occur frequently in human malignancies. There have been varied reports on their prevalence and hence their likely significance in the pathogenesis of primary thyroid neoplasia. To address this, we have examined a large series of benign and malignant thyroid tumours for ras mutations.DESIGNGenomic DNA was analysed for the presence of mutations at codons 12, 13 and 61 of H‐ras, K‐ras and N‐ras by allele‐specific oligonucleotide hybridization. Direct DNA sequencing was used to confirm the mutations.PATIENTSA total of 90 samples with benign (66) and malignant (24) thyroid disease were investigated.RESULTSA total of 14/90 (15.5%) samples had a ras mutation. All mutations were at codon 61 of either N‐ras or K‐ras. The positive cases were 1/25 (4%) nodular goitre, 7/38 (18%) follicular adenoma, 4/9 (44%) follicular carcinoma, 1/1 anaplastic carcinoma, 1/1 follicular variant of papillary carcinoma, and 1 metastatic follicular carcinoma in which the primary tumour had the same mutation.CONCLUSIONSOur data demonstrate a relatively low overall prevalence of ras mutations in thyroid neoplasia, with a predominance in follicular neoplasms. Their presence in follicular adenomas suggests that they may have an early aetiological role in the development of thyroid neoplasia.
Long‐term substitution therapy of hypogonadal men with transscrotal testosterone over 7–10 years
Authors: Behre Hermann M. , Von Eckardstein Sigrid , Kliesch Sabine , Nieschlag Eberhard 
Published: March 2003

OBJECTIVETestosterone (T) substitution of hypogonadal men by conventional intramuscular injection of T esters is not considered optimal because it induces unphysiologically fluctuating serum T levels. In contrast, scrotal T patches produce normal serum (T) levels mimicking diurnal variations. In order to assess the quality of this new form of T substitution we followed hypogonadal men treated by transdermal T up to 10 years.PATIENTSEleven men aged 35.9 ± 9.8 years (mean ± SD) at the beginning of the study were treated with transscrotal T patches (Testoderm®) because of primary (n = 4) or secondary (n = 7) hypogonadism. Clinical examinations were performed every 3 months during the first 5 years and every 6 months thereafter. All 11 patients were seen for 7 years and some for longer periods: eight for 8 years, six for 9 years and four for 10 years.MEASUREMENTS AND RESULTSWith daily application of one patch T levels rose from 5.3 ± 1.3 nmol/l (mean ± SE) to 16.7 ± 2.6 nmol/l at month 3 and remained in the normal range throughout treatment. Serum 5α‐dihydrotestosterone (DHT) rose from 1.3 ± 0.4 nmol/l to 3.9 ± 1.4 nmol/l and oestradiol from 52.3 ± 9.3 to 71.3 ± 9.6 pmol/l and remained stable without significant variations throughout the observation period. Patients reported absence of local side‐effects except for occasional itching. No relevant changes occurred in clinical chemistry, including total cholesterol levels and triglycerides. Haemoglobin and erythrocyte counts remained normal. Bone density measured by QCT increased slightly from 113.6 ± 5.4 to 129.7 ± 9.3 mg/cm3 during the observation period (P = 0.028). In the nine patients aged < 50 years prostate volumes showed a small but insignificant increase from 16.8 ± 1.5 to 18.8 ± 2.1 ml during transscrotal T therapy. In the two older patients prostate volume remained constant or decreased slightly during T therapy after an initial increase in the previously untreated patient. Prostate specific antigen levels were constantly low in all patients.CONCLUSIONTransscrotal testosterone patches are well‐accepted and safe in long‐term testosterone substitution therapy for male hypogonadism.
Hypothalamic derangement in traumatized patients: growth hormone (GH) and prolactin response to thyrotrophin‐releasing hormone and GH‐releasing hormone
Authors: De Marinis  , Mancini  , Valle  , Bianchi  , Gentilella  , Liberale  , Mignani  , Pennisi  , Della Corte  
Published: March 2003

OBJECTIVETo study the impact of severe head injury on both basal pituitary hormone secretion and the response to exogenous synthetic hypothalamic releasing factors (TRH and GHRH) in order to evaluate sequential changes in the central control of hypophyseal secretion in the days following head injury.DESIGNProspective clinical studyPATIENTS21 comatose male patients with head injuries, each intubated and ventilated, intensively monitored and having no previous endocrine problems.MEASUREMENTSAND RESULTS The GH and PRL responses to TRH (200 μg iv), and the GH and PRL responses to GHRH (50 μg iv) were evaluated, respectively, on the days 1 and 16 and on days 2, 7and 15 after admission. Daily blood samples were also collected for GH, PRL, TSH, T3 and T4 evaluation. In the basal samples taken on days 2, 7 and 15, IGF‐I and cortisol were also determined. Nitrogen balance was assessed daily. On the day 1, TRH increased GH levels from 9.8 ± 2.2 to 22.4 ± 6.5 mU/l but failed to induce GH release on day 16. The PRL response to TRH was normal. The GH peak response to GHRH was normal on the day 2 (35.7 ± 13.9 mU/l), but was increased on days 7 and 15 (68.3 ± 10.7 mU/l on day 7; 73.8 ± 9.2 mU/l on day 15, P < 0.01 vs. day 2). We found a significant PRL response to GHRH during the whole period of observation. In the daily evaluation, nitrogen balance was negative in all patients from the day 1 to 5. On average, all patients reached a positive nitrogen balance on the day 8. Compared to the day 2, a statistical increase in IGF‐I concentration was observed on days 7 and 15.CONCLUSIONSThe evaluation of pituitary dynamics in the acute phase of a severe injury demonstrates an alteration of GH and PRL secretion, which correlate with the aminergic and/or peptidergic derangements. Taken together, our data suggest augmented tone of both GHRH and somatostatin in the very acute phase, while an imbalance of releasing factors is hypothesized in the following days. The metabolic consequences of this neuroendocrine pattern could be advantageous in the rapid recovery from the cascade of events produced by the trauma, as documented by the increase in IGF‐1 levels and the positive nitrogen balance.
Macroprolactinaemia: validation and application of the polyethylene glycol precipitation test and clinical characterization of the condition
Authors: Olukoga  , Kane  
Published: March 2003

OBJECTIVEThe clinical characteristics and natural history of macroprolactinaemia are yet to be fully established and there is currently no widely accepted simple in vitro test for routine identification of the condition. This study was designed to further validate the polyethylene glycol (PEG) precipitation test with assessment of percentage prolactin recovery (%R), for the detection of macroprolactinaemia and clinically characterize cases identified using the test.DESIGNAnalytical validation and application of the PEG precipitation test for diagnosis of macroprolactinaemia and a retrospective case‐notes review of some of the patients identified with the condition.PATIENTSSera from 188 patients with elevated serum prolactin (PRL) concentrations were screened for macroprolactinaemia. Seventeen of the patients who were under follow‐up at the local teaching hospital and were identified to have macroprolactinaemia were systematically characterized clinically.MEASUREMENTSProlactin was measured in sera, fractions from gel filtration chromatography and supernatant obtained after PEG precipitation, by the DELFIA fluoroimmunoassay.CLINICAL ENDPOINTSInitial serum PRL and symptoms and their response to dopamine agonist therapy; imaging of the pituitary gland; serum PRL and symptoms after cessation of dopamine agonist therapy; course of serum PRL and symptoms without dopamine agonist therapy.RESULTSThe within‐batch coefficient of variation (CV) of the PEG precipitation test ranged between 2.8 and 7.3% while the between‐batch CV ranged between 3.4 and 9.7%. Intra‐individual variability up to five months was 9.9%. A prolactin recovery ≤ 40% was indicative of macroprolactinaemia, while the condition was unlikely to be present at values > 50%. The prevalence of macroprolactinaemia was 15% without sex difference. Clinical characterization of 17 patients showed modest initial serum PRL concentrations and there was imaging evidence of a coexisting pituitary adenoma in three of them. Dopamine agonist therapy resulted in substantial falls in serum PRL and this was associated with improvement or resolution of symptoms in some patients. Stoppage of dopamine agonist resulted in rebound hyperprolactinaemia in all cases. Spontaneous improvement in symptoms occurred in three patients but hyperprolactinaemia persisted in all those who were not on treatment.CONCLUSIONSThe PEG precipitation test with assessment of ‘free’ prolactin has been shown to be reproducible and sensitive for the detection of macroprolactinaemia. Many of the patients who had macroprolactinaemia presented with at least one symptom of the hyperprolactinaemic syndrome. Dopaminergic therapy may influence the course of both serum PRL and symptoms in some of these patients.
p16 (INK4a, MTS‐1) gene polymorphism and methylation status in human pituitary tumours
Authors: Jaffrain‐Rea  , Ferretti  , Toniato  , Cannita  , Santoro  , Di Stefano  , Ricevuto  , Maroder  , Tamburrano  , Cantore  , Gulino  , Martinotti  
Published: March 2003

OBJECTIVEThe p16 gene, which encodes a physiological inhibitor of the cyclin D‐CDK4 complex, is now considered as an important tumour‐suppressor gene in a variety of tumours. A marked reduction of its expression has been reported to occur without significant genetic alterations in human pituitary adenomas, although rare point mutations of uncertain functional significance have been described. On the other hand, p16 gene silencing due to hypermethylation has been reported in several human primary tumours. The aim of this study was to further investigate the pathogenetic events leading to p16 gene inactivation in pituitary tumours.DESIGNTo screen a european series of human pituitary tumours for p16 gene alterations and possible gene hypermethylation.PATIENTSA representative series of 31 human pituitary tumours—30 macroadenomas, including a MEN‐1 non‐secreting pituitary adenoma and a non‐MEN‐1 familial giant GH‐secreting adenoma, and one FSH‐secreting pituitary carcinoma—was studied.METHODSPolymerase chain reaction/single strand conformation polymorphism (PCR‐SSCP) analysis was used to screen for p16 gene alterations in all cases. Direct sequencing of PCR‐products was obtained by the di‐deoxynucleotide method where suspected abnormalities of the PCR‐SSCP analysis were observed. In 24 samples, a methylation‐specific PCR assay (MSP‐PCR) was used to determine p16 gene methylation status.RESULTSTwo sporadic cases of pituitary adenomas had a similar single A to G base substitution leading to an heterozygous Ala140Thr p16 polymorphism, which has not previously been described in such tumours, but is known to be functionally silent. No other p16 abnormality could be suspected from PCR‐SSCP analysis in this series. In contrast, the presence of methylated‐specific PCR products was observed in 20/24 cases (83.3%).CONCLUSIONSThis study confirms that p16 gene mutations are not involved in the pathogenesis of human pituitary tumours, although polymorphisms can be demonstrated, depending on the population considered. In contrast, the high incidence of hypermethylation of the p16 gene suggests that such an alteration occurs early in pituitary tumours, and may play a role in pituitary tumorigenesis.
Frequent loss of heterozygosity at chromosome 3p14.2–3p21 in human pancreatic islet cell tumours
Authors: Nikiforova Marina N. , Nikiforov Yuri E. , Biddinger Paul , Gnepp Douglas R. , Grosembacher Luis A. , Wajchenberg Bernardo L. , Fagin James A. , Cohen Robert M. 
Published: March 2003

OBJECTIVEPancreatic islet βcell tumours occur either sporadically or as part of inherited neoplastic syndromes, most commonly multiple endocrine neoplasia (MEN) type 1. Recently, a transgenic mouse model has been established in which the expression of the SV40 large T antigen was targeted to βcells by the rat insulin promoter, leading to the development of multiple pancreatic βcell tumours. In the advanced stages of tumour evolution, these tumours exhibited a high prevalence of loss of heterozygosity (LOH) on mouse chromosomes 9 and 16, at regions syntenic with regions 3q, 3p21, 6q12, 15q24 and 22q of the human genome.DESIGNLoss of heterozygosity in human islet cell tumours was analysed in a PCR based approach at regions of the human genome syntenic with the mouse loci linked to pancreatic βcell tumours as well as the MEN1 gene on chromosome 11q13. These included 35 microsatellite markers in the human chromosomal regions 3q, 3p21, 6q12, 11q13, 15q24 and 22q.PATIENTS21 patients diagnosed with insulinoma were analysed. Histologically, 16 tumours were benign, while 5 were malignant insulinomas.RESULTSThirteen of 21 (62%) tumours were found to have loss of genetic material on chromosome 3. The shortest region of overlap implicated a deletion at 3p14.2–3p21 region, corresponding to the marker D3S1295. We did not detect a substantial frequency of LOH in the other syntenic regions, except for the region of MEN 1 gene on 11q13 found to be deleted in 6 (29%) cases, including 3 of 4 tumours from MEN 1 families. Deletions of 3p14.2–3p21 were observed in 8 of 15 (53%) benign tumours, and in 5 of 6 (83%) malignant neoplasms.CONCLUSIONSThese results indicate the high frequency of 3p14.2–3p21 deletions in human pancreatic βcell neoplasms. These finding suggest the presence of a tumour suppressor gene in this region, that may be important in the microevolution of these tumours towards malignancy.
Acute dexamethasone administration enhances GH responsiveness to GH releasing peptide‐6 (GHRP‐6) in man
Authors: Pinto Ana‐Cláudia A. R. , Finamor Jr Francisco E. , Lengyel Ana‐Maria J. 
Published: March 2003

OBJECTIVEAcute administration of glucocorticoids stimulates GH secretion probably by a decrease in hypothalamic somatostatin release. GHRP‐6 is a synthetic hexapeptide that increases GH secretion by a mechanism of action not yet fully known, but apparently not by inhibition of hypothalamic somatostatin release. The aim of this study was to evaluate the effect of acute dexamethasone administration on GH responsiveness to GHRP‐6 in man.DESIGNOne group of subjects received iv GHRP‐6 (1 μg/kg), GH‐releasing hormone (GHRH; 100 μg), GHRH plus GHRP‐6 or saline 3.5 h after oral acute dexamethasone administration (4 mg; at 0600 h). A second study group was treated with GHRP‐6, GHRH or GHRP‐6 plus GHRH after placebo ingestion, following the same protocol.PATIENTSSixteen normal subjects (mean age: 29 ± 3.3 years), with normal BMI (22.4 ± 2.0 kg/m2), were studied. Eight subjects received dexamethasone and the other eight were treated with placebo.MEASUREMENTSSerum GH was measured by a two site monoclonal antibody immunofluorometric assay.RESULTSIn the placebo‐treated subjects, mean peak GH (mU/l; mean ± SE) and AUC (mU.min/l) values after GHRP‐6 administration (peak: 43.8 ± 9.0; AUC: 2262.0 ± 459.2) did not differ from those observed after GHRH injection (peak: 49.8 ± 12.0; AUC: 2903.4 ± 872.6). The association of the two peptides markedly increased GH levels (peak: 172.4 ± 34.2; AUC: 10393.0 ± 1894.8) compared with the isolated administration of GHRP‐6 or GHRH. In the subjects who received dexamethasone 3.5 h before saline injection, GH baseline values were significantly higher than those observed after 90 min of sampling (12.4 ± 9.4 vs. 4.6 ± 2.0). Mean GH peak and AUC values after GHRP‐6 (peak: 78.8 ± 11.0; AUC: 4114.6 ± 588.2) and after GHRH administration (peak: 46.8 ± 16.0; AUC: 3006.8 ± 1010.0) did not differ significantly in the dexamethasone‐treated subjects. In this study group, the administration of the two peptides together caused a significant increase in both peak (119.2 ± 16.0) and AUC values (7377.0 ± 937.2) compared with the response obtained after each peptide alone. When the two groups were compared, a significant increase in GH responsiveness to GHRP‐6 was observed after dexamethasone administration compared with placebo. No differences in GH response to GHRH, or to the administration of the two peptides together, were seen between the two groups.CONCLUSIONSOral dexamethasone, at a dose of 4 mg, enhances GH releasing peptide‐6‐induced GH release when administered 3.5 h earlier. These results suggest that dexamethasone and GHRP‐6 could act at different sites of GH releasing mechanisms. Further studies are necessary to elucidate these findings.
Hypoglycaemia associated with the production of insulin‐like growth factor II and insulin‐like growth factor binding protein 6 by a haemangiopericytoma
Authors: Hoekman Klaas , Van Doorn Jaap , Gloudemans Ton , Maassen Johannes A. , Schuller Alwin G. P. , Pinedo Herbert M. 
Published: March 2003

Non‐islet‐cell tumour‐induced hypoglycaemia (NICTH) is, in most cases, attributable to tumour production of insulin‐like growth factor II (IGF‐II). Tumour‐derived IGF‐II has a higher than normal molecular weight (big ‘IGF‐II’) and an impaired ability to form the normal ternary 150 kD complex with IGF binding protein‐3 (IGFBP‐3) and the acid‐labile subunit (ALS). Consequently, tumoral IGF‐II circulates mainly in smaller binary complexes which have a higher bioavailability than the ternary complex.We had the opportunity to analyze IGFs and IGF‐related factors in both pre‐ and post‐operative blood, tumour tissue and tumour cyst fluid from a patient with a disseminated haemangiopericytoma and severe hypoglycaemia. In addition, the effect of serum and tumour cyst fluid on autophosphorylation of the insulin receptor was examined.Patient serum contained low levels of IGF‐I, IGFBP‐3 and ALS, while the concentrations of IGFBP‐2 and IGFBP‐6 were markedly elevated. The total level of circulating IGF‐II was within the normal range, but Biogel P‐60 gel filtration of patient serum revealed that 77% of the IGF‐II was present in high molecular weight forms (normal: 10–15%), which decreased to 53% after partial removal of the tumour. Most of the IGF‐II immunoreactivity in pre‐ and post‐operative patient serum was associated with 50–60 kD complexes with only a minimal contribution (<10%) from the 150 kD complex. Tumour cyst fluid contained excessive amounts of both big IGF‐II and IGFBP‐6.Northern blot analysis of total mRNA isolated from the tumour demonstrated high expression of the IGF‐II gene and abundant 1.1 kb IGFBP‐6 transcript, while the genes encoding IGFBP‐3, ‐4 and ‐5 were only weakly expressed and mRNA of IGFBP‐1, ‐2 and IGF‐I could not be detected. mRNAs for the IGF type II receptor could be easily demonstrated, whereas those for the insulin‐ and IGF type I receptor were hardly detectable. In contrast to patient serum tumour cyst fluid strongly stimulated the insulin receptor in vitro. The present study suggests an important role of the simultaneous production of IGF‐II and IGFBP‐6 in the pathophysiology of tumour‐induced hypoglycaemia.
Absence of somatostatin receptor type 2 A mutations and gip oncogene in pituitary somatotroph adenomas
Authors: Petersenn Stephan , Heyens Maria , Lüdecke Dieter K. , Beil Frank U. , Schulte Heinrich M. 
Published: March 2003

OBJECTIVESomatostatin, acting via specific receptors in the anterior pituitary, tonically inhibits pituitary growth hormone secretion and somatotroph proliferation. Reduction of growth hormone secretion and tumour regression in GH‐secreting pituitary adenomas treated with long‐acting somatostatin analogues varies widely. In 30–40% of these tumours dominant somatic mutations of the Gsα gene (gsp) have been demonstrated leading to constitutive adenylyl cyclase induction. A relationship between somatostatin sensitivity and tumour pathogenesis in some tumours has been suggested. Changes in the function of the somatostatin receptor or intracellular signal elements may be of relevance. Somatostatin receptor type 2 A (sst2A) and Gi2 are proposed to mediate selectively the inhibition of GH release in the somatotroph. We therefore investigated the presence of sst2A mutations and gip oncogene in somatotrophic pituitary adenomas.DESIGNTumour samples from 15 patients with pituitary somatotroph adenomas were obtained. RNA was isolated and used for reverse transcription and subsequent polymerase chain reaction. All samples were screened for the presence of sst2A mutations and of the gip oncogene by SSCP analysis and sequencing. For comparison, the gsp oncogene was examined. The relationship between clinical data and molecular analysis results was investigated.RESULTSSeven of the tumours harboured a gsp mutation. No mutations affecting the sst2A protein were found in any of the tumours analysed. Furthermore, gip oncogene was absent in all tumours.CONCLUSIONMutations of the somatostatin receptor type 2 A and the gip oncogene are unlikely to be involved in the pathogenesis of acromegaly.