bluuebunny/crossref_metadata_2025 huggingface dataset:
Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men
Authors: Pfeifer Marija , Kanc Karin , Verhovec Renata , Kocijančič Andreja
Published: March 2003

OBJECTIVE The within subject variability of the insulin tolerance test (ITT) for assessment of growth hormone (GH) status and cortisol reserve has rarely been examined, particularly in patients with hypopituitarism. This becomes important when biochemical criteria are used to determine which adults with hypopituitarism should receive GH and/or cortisol replacement. In the present study we assessed the reproducibility of GH and cortisol responses in repeated ITTs. Baseline insulin‐like growth factor 1 (IGF‐1) levels were also assessed for reproducibility on each occasion.

DESIGN and PATIENTS Three consecutive ITTs were performed in seven normal adult men (ages 22–27 years) and two ITTs in 11 men with hypopituitarism and suspected GH deficiency (ages 23–48 years).

MEASUREMENTS Serum GH and IGF‐1 were measured by immunoradiometric and cortisol by immunofluorimetric assays.

RESULTS In normal men group peak GH responses did not differ between the three tests. There was no correlation between individual peak values. The within subject peak GH variability was between 4·6 and 59·3%, and the overall variability in 21 tests was 35%. The lowest peak GH concentration was 70 mU/l (27 µg/l). All hypopituitary men had severe GH deficiency (all peak GH concentrations < 4 mU/l (1·5 µg/l) in both tests). There was a highly significant correlation between individual peak GH values (r = 0·95, P < 0·0001). Basal IGF‐1‐values in normal and hypopituitary men were highly correlated between tests (r = 0·98, P < 0·0001). The overall within subject variability of IGF‐1‐values was 11·9% in normal and 22·7% in hypopituitary men. In normal men group peak cortisol responses were not different between the three tests. There was a good correlation between individual peak cortisol responses in the three ITTs. The within subject peak cortisol variability (median 8·3%; range 0·7–21·5%) was significantly less than that of GH (P < 0·03) in two of three test comparisons. In hypopituitary men the within subject peak cortisol variability (median 41·6%; range 3·5–92·7%) was significantly greater (P < 0·001) than in normal men. All patients were correctly classified as cortisol deficient or normal in both ITTs.

CONCLUSION The cortisol response to repeated hypoglycaemia is very reproducible in normal men but the GH response is less so. In hypopituitary men the reproducibility of the GH response is good while that of the cortisol response is poor. However, a single ITT did not misclassify hypopituitary patients who are severely GH and/or ACTH deficient and was therefore adequate for clinical decisions regarding GH and/or cortisol replacement. Nevertheless, it remains possible that a single ITT could misclassify some hypopituitary patients with partial GH or ACTH deficiency.
Effects of insulin and glucocorticoids on the leptin system are mediated through free leptin
Authors: Lewandowski K. , Randeva H.S. , O'Callaghan C.J. , Horn R. , Medley G.F. , Hillhouse E.W. , Brabant G. , O'Hare P.
Published: March 2003

OBJECTIVE Insulin and glucocorticoids are known to increase total leptin levels. However, the effects of insulin and glucocorticoids on the components of the leptin system – free leptin (FL), bound leptin (BL) and soluble leptin receptor (SR) – have not been elucidated. The aim of this study was to determine if there is a differential effect of insulin and glucocorticoids on the leptin system.

MATERIAL AND METHODS In the first of two studies (study 1), we measured free leptin (FL), bound leptin (BL), a soluble leptin receptor (SR) and insulin, by specific RIA methods, in six healthy subjects on a control day, and subsequently during a hyperinsulinaemic euglycaemic clamp study. In the second study (study 2) we measured the same parameters in six healthy subjects, before (day 1) and during administration of dexamethasone over 3 consecutive days.

RESULTS In study 1, on the control day FL levels rose over the 16 h monitoring period (P = 0·057) and SR levels declined (P < 0·001), but there was no change of BL levels. Even after accounting for diurnal variation, FL levels increased even more substantially over 12 h of insulin infusion than observed on the control day (P < 0·001). In study 2, mean FL concentration doubled from day 1 to day 2 (P = 0·01) and remained elevated subsequently. In contrast to FL, BL and SR levels remained unchanged during the study. Fasting insulin levels (pmol/l) increased from day 1 to day 2, but this rise only approached significance on day 4 (P = 0·05).

CONCLUSION We conclude that insulin and dexamethasone increase free leptin levels, but do not change the concentrations of bound leptin and soluble leptin receptor. Furthermore, the dexamethasone‐induced rise in leptin levels is (at least partially) independent of the effects of glucocorticoid‐induced hyperinsulinaemia.
Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma
Authors: Schott Matthias , Feldkamp Joachim , Lettmann Melanie , Simon Dietmar , Scherbaum Werner A. , Seissler Jochen
Published: March 2003

OBJECTIVE Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell‐based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin‐producing pancreatic carcinoma.

DESIGN Autologous dendritic cells (DCs) were generated from peripheral blood monocytes in the presence of granulocyte/macrophage colony‐stimulating factor, interleukin‐4 and tumour necrosis factor α. DCs were loaded with tumour‐derived lysate (TL), and were delivered by subcutaneous injections in 4‐week intervals.

RESULTS Three weeks after first treatment, the patient developed a strong delayed‐type hypersensitivity (DTH) skin reaction with an erythema and induration after the challenge with TL‐pulsed DCs, which indicates the efficient generation of antigen‐specific memory T‐cells. Immunohistochemical analysis of skin biopsy demonstrated a strong perivascular and epidermal infiltration by T‐helper (CD4 positive) and cytotoxic T cells (CD8 positive). Stimulation with TL revealed a dose‐dependent T‐cell proliferation with a stimulation index of 1·1–5·7 compared to 1·1–1·4 before vaccination (P < 0·01). Most strikingly, DC‐based vaccination was accompanied by a steady decrease of the tumour marker chromogranin A from 2.93 umol/l initially to below the detection limit of 0.15 umol/l within 9 months of therapy. The ultrasound examination revealed a tumour regression of the metastasis in the right lobe of the liver.

CONCLUSIONS Our data indicate that vaccination with tumour lysate‐pulsed DCs induced a significant antitumour immune response in a neuroendocrine carcinoma of the pancreas. This approach represents an alternative strategy for the treatment of advanced neuroendocrine carcinomas that are resistant to conventional therapy.
Efficacy of radiotherapy in normalizing serum IGF‐I, acid‐labile subunit (ALS) and IGFBP‐3 levels in acromegaly
Authors: Epaminonda Paolo , Porretti Silvia , Cappiello Vincenzo , Beck‐Peccoz Paolo , Faglia Giovanni , Arosio Maura
Published: March 2003

OBJECTIVE Radiotherapy (RT) has been used for many years in order to complete the cure of unsuccessfully operated acromegalic patients. Several studies have shown its efficacy in normalizing GH levels, while reports about IGF‐I normalization are conflicting. Moreover, data regarding other markers of disease activity, such as IGFBP‐3 and acid‐labile subunit (ALS), i.e. the other two components of the circulating 150 kDa complex, are lacking.

DESIGN Retrospective study.

PATIENTS AND MEASUREMENTS Sixty‐seven acromegalic patients (20 males and 47 females, aged 40 ± 6 years) who underwent postoperative RT (in fractionated doses for a total of 40–75 Gy) were followed‐up for 11 ± 6 years (range: 1–26 years, median: 10 years). Serum GH and IGF‐I levels off medical therapy were measured in all patients; ALS and IGFBP‐3 were measured in 11 patients with normalization of IGF‐I concentrations. Computed tomography or nuclear magnetic resonance imaging periodically assessed possible development of pituitary deficiency along with imaging of the hypothalamic‐pituitary region.

RESULTS Forty‐one out of 67 patients (58%) achieved GH levels < 2·5 µg/l by 1–15 years after RT (mean 8 ± 6) and 37/67 patients (55%) had normal or low IGF‐I levels 1–26 years after RT (mean: 12 ± 6), a normalization of both parameters being seen in 37 patients. GH < 2·5 µg/l and normal IGF‐I levels were achieved in 17/26 (65%) patients followed‐up for at least 15 years. ALS and IGFBP‐3 concentrations paralleled IGF‐I levels in all patients studied. With respect to secondary pituitary insufficiency, acquired ACTH deficiency was found in 25 patients, TSH deficiency in 20, gonadotropin deficiency in 23 and GH deficiency in seven. In total, two cases of meningioma and one pineal tumour, possibly related to RT, were seen 9–22 years after RT.

CONCLUSIONS RT is an effective, although slow‐acting, therapeutic tool for acromegaly, with ‘safe’ GH levels and normal IGF‐I concentrations being achieved in 65% of patients after 15 years. IGF‐I levels normalize more slowly than GH levels. Radiotherapy is able to normalize the concentration of all three components of the circulating 150 kDa complex. Checks for loss of pituitary function and appearance of second brain tumours must be carried out life‐long.
Octreotide LAR® treatment throughout pregnancy in an acromegalic woman
Authors: Fassnacht Martin , Capeller Barbara , Arlt Wiebke , Steck Thomas , Allolio Bruno
Published: March 2003

We report a 24‐year‐old woman with active acromegaly despite pituitary surgery and irradiation who received continuous octreotide LAR® treatment for the control of GH excess throughout her pregnancy. The patient delivered a healthy girl following an uneventful pregnancy. Despite a substantial materno–fetal transfer of octreotide, postnatal development was normal with length parameters around the 50th percentile at 3 months of age. In almost all previously described cases (n = 13) octreotide was stopped after the diagnosis of pregnancy was established. No side‐effects of mother or fetus have been reported. Octreotide treatment in pregnancy seems to be feasible and safe. Due to the still‐limited number of reported cases, the potential benefits of octreotide treatment should be weighed carefully against its possible risks.
Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with 131I‐meta‐iodobenzylguanidine (131I‐mIBG)
Authors: Mukherjee J. J. , Kaltsas G. A. , Islam N. , Plowman P. N. , Foley R. , Hikmat J. , Britton K. E. , Jenkins P. J. , Chew S. L. , Monson J. P. , Besser G. M. , Grossman A. B.
Published: March 2003

OBJECTIVE Meta‐iodo‐benzyl‐guanidine labelled with 131‐iodine (131I‐mIBG) has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non‐catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of 131I‐mIBG, we have reviewed all patients who had received this form of treatment in our department.

DESIGN Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with131I‐mIBG and were followed‐up according to a defined protocol in a given time frame.

PATIENTS Thirty‐seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with 131I‐mIBG over a 15‐year period were included in this analysis.

MEASUREMENTS The symptomatic, hormonal and tumoural responses before and after 131I‐mIBG therapy over a median follow‐up duration of 32 months (range 5–180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18–81 years), 15 were treated with 131I‐mIBG alone whereas the other 22 received additional therapy.

RESULTS A total of 116 therapeutic 131I‐mIBG doses were administered [mean cumulative dose 592 mCi (21·9 GBq); range 200–1592 mCi (7·4–58·9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with 131I‐mIBG alone and 84% who received additional therapy showed stable disease over the period of follow‐up. Overall survival during the period of the study was 71%. The overall 5‐year survival rate was 85% (95% confidence interval, 72–99%) for all patients and 78% (95% confidence interval, 55–100%) for the carcinoid group alone, according to Kaplan–Meier analysis. Symptomatic control was achieved in all the patients treated with 131I‐mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. 131I‐mIBG therapy was safe and well tolerated. Serious side‐effects necessitating the termination of 131I‐mIBG therapy were seen in only 2 of our patients.

CONCLUSIONS  131I‐mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.
Association of polymorphic alleles of the calcium‐sensing receptor gene with the clinical severity of primary hyperparathyroidism
Authors: Yamauchi Mika , Sugimoto Toshitsugu , Yamaguchi Toru , Yano Shozo , Kanzawa Michiko , Kobayashi Akira , Chihara Kazuo
Published: March 2003

OBJECTIVE Primary hyperparathyroidism (pHPT) is a heterogeneous disease in its clinical course and severity. Previous studies have suggested an association between the clinical severity of pHPT and the genotypes of vitamin D receptor, oestrogen receptors and PTH molecules. The Ca‐sensing receptor (CaR) is activated by an extracellular calcium ion and controls PTH secretion, and thus polymorphisms of CaR might be associated with the magnitude of PTH secretion and the clinical severity of pHPT. In this study, we examined the relationship between CaR polymorphisms and biochemical markers in pHPT patients.

METHODS We analysed 105 Japanese pHPT patients (85 females and 20 males; mean age 55·6 ± 14·0 years). We determined the CaR genotypes of G990R and intron 5 polymorphisms with genomic DNA extracted from peripheral lymphocytes. The intron 5 polymorphism was defined as T/T, T/C and C/C.

RESULTS In the G990R polymorphism, serum levels of both intact PTH and alkaline phosphatase (ALP) were significantly higher and the serum level of phosphorus was significantly lower in the RR group than in the GG group. In the intron 5 polymorphism, the T/T group showed significantly lower serum levels of intact PTH and Ca. Furthermore, patients with both the codon 990 RR and the intron 5 C allele (the RRC+ group) had significantly higher serum levels of intact PTH and ALP than did the other patients.

CONCLUSIONS The present study is the first to show that CaR polymorphisms of G990R and intron 5 were closely associated with the magnitude of PTH secretion and/or PTH degradation as well as the clinical severity in pHPT patients.
Plasma leptin in chronic fatigue syndrome and a placebo‐controlled study of the effects of low‐dose hydrocortisone on leptin secretion
Authors: Cleare A. J. , O'Keane V. , Miell J.
Published: March 2003

OBJECTIVEPrevious studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS.

DESIGN(i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo‐controlled crossover study of the effects of hydrocortisone on leptin levels in CFS.

PATIENTSThirty‐two medication free patients with CFS but not comorbid depression or anxiety. Thirty‐two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls.

MEASUREMENTSWe measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo‐controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo.

RESULTSAt baseline, there was no significant difference in plasma leptin between patients [mean 13·8, median 7·4, interquartile range (IQR) 18·0 ng/ml] and controls (mean 10·2, median 5·5, IQR 11·3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment‐responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone‐induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS.

CONCLUSIONSWe conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.
Effect of long‐term administration of recombinant human growth hormone (rhGH) on plasma erythropoietin (EPO) and haemoglobin levels in anaemic patients with adult GH deficiency
Authors: Sohmiya Motoi , Kato Yuzuru
Published: March 2003

OBJECTIVE We investigated the effect of recombinant human GH (rhGH) on erythropoietin (EPO) and haemoglobin (Hb) concentrations in anaemic patients with adult GH deficiency.

PATIENTS AND DESIGN rhGH was administrated in 8 patients with adult GH deficiency, three males and five females, aged from 24 to 69 years, mean (± SD) of 48·8 ± 16·4 years, for 1 year by means of continuous subcutaneous infusion (CSI) at a flow rate of 0·036 U/kg/day using a portable syringe pump. Blood samples were obtained in the morning after an overnight fast every week for 1 month, followed by each month before and after the start of rhGH administration.

RESULTS Mean (± SE) plasma GH levels increased from 0·24 ± 0·09 µg/l to 2·32 ± 0·23 µg/l 1 week after the start of rhGH administration to maintain a steady state. Plasma IGF‐I levels increased from 70·1 ± 13·8 µg/l to 282·8 ± 70·6 µg/l 1 week after the start of rhGH administration to maintain the steady state. Plasma EPO levels increased from 25·9 ± 2·6 IU/l to 37·6 ± 4·2 IU/l and 34·3 ± 3·6 IU/l at 1 week and 2 weeks after the start of rhGH administration, respectively, and then decreased gradually to 14·9 ± 2·1 IU/l at 10 months after the start of rhGH administration. Reticulocyte counts increased from 0·88 ± 0·06% to 1·49 ± 0·21% at 1 week. Hb concentrations increased from 103 ± 5 g/l to 106 ± 5 g/l at 2 weeks after the start of rhGH administration, and then increased gradually to reach the normal range.

CONCLUSIONS We conclude that EPO secretion was stimulated in the initial 2 weeks after the start of CSI of rhGH in anaemic patients with adult GH deficiency. Increased Hb concentrations after long‐term administration of rhGH might be explained by direct stimulatory effects of rhGH and IGF‐I on erythroid cells, which was accompanied by suppressed EPO secretion, in combination with a more generalized indirect impact of rhGH on physical activety. These findings suggest a beneficial effect of rhGH replacement in anaemic patients with adult GH deficiency.
Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel α1 subunit gene (Cav1·1) are not associated with thyrotoxic hypokalaemic periodic paralysis
Authors: Dias da Silva Magnus R. , Cerutti Janete M. , Tengan Célia H. , Furuzawa Gilberto K. , Vieira Teresa C. A. , Gabbai Alberto A. , Maciel Rui M. B.
Published: March 2003

objective To investigate whether patients with thyrotoxic hypokalaemic periodic paralysis (THPP) have the same molecular defect in the calcium channel gene described in familial hypokalaemic periodic paralysis (FHPP), as the symptoms of both diseases are comparable, we analysed, in patients with THPP, the presence of mutations R528H, R1239H and R1239G on the S4 voltage‐sensing transmembrane segment of the α1 subunit of the calcium channel gene (Cav1·1).

design and patients Genomic DNA was extracted from peripheral blood from 14 patients with THPP, 13 sporadic cases and one with a family history. An FHPP family was selected as a positive control. The exons bearing the described mutations were amplified by PCR, screened by single‐strand conformation polymorphism (SSCP), and further sequenced.

measurements THPP was diagnosed both clinically and through laboratory tests, all patients having elevated levels of thyroid hormones (T4, T3 or free T4), suppressed TSH and plasma potassium below 3·5 mmol/l.

results No evidence of the described mutations was found in patients with THPP. Furthermore, we did not detect any mutations in any of the four full S4 voltage‐sensing transmembrane segments of Cav1·1 (DIS4, DIIS4, DIIIS4 and DIVS4) by direct sequencing. However, close to the R528H mutation, we identified two single nucleotide polymorphisms at nucleotides 1551 and 1564 in both familial and sporadic cases with THPP. In addition, we were able to detect the R528H mutation in the DIIS4 transmembrane segment in all members of the FHPP family.

conclusion Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel α1 subunit gene (Cav1·1) are not associated with thyrotoxic hypokalaemic periodic paralysis. However, polymorphisms in nucleotides 1551 and 1564 in the exon 11 were found in patients with familial hypokalaemic periodic paralysis and thyrotoxic hypokalaemic periodic paralysis in higher frequency than in controls. The polymorphisms identified within the Cav1·1 gene are associated with thyrotoxic hypokalaemic periodic paralysis and represent a novel finding.
Effects of GH on lipid peroxidation and neutrophil superoxide anion‐generating capacity in hypopituitary adults with GH deficiency
Authors: Smith J. C. , Lang D. , McEneny J. , Evans L. M. , Scanlon M. F. , Young I. , Davies J.
Published: March 2003

objectives  Untreated growth hormone deficiency (GHD) is implicated in the increased cardiovascular risk associated with adult hypopituitarism. Oxidative stress, predisposing to lipid peroxidation, may be an important mediator of endothelial dysfunction, a pro‐atherogenic state associated with adult GHD.

design and patients In a randomized, double‐blind, placebo‐controlled study we investigated the effects of GH replacement on low‐density lipoprotein (LDL) oxidation and neutrophil superoxide (O2−) generating capacity in 32 GHD adults (19 males, 13 females; age range 19–64 years) over 3 months. Thirty age‐ and sex‐matched healthy controls were also studied.

measurements Lipid hydroperoxides (HPOs) in plasma were measured using the ferrous oxidation with xylenol orange (FOX) assay. The susceptibility of LDL to oxidation was assessed by the copper‐catalysed lag phase of LDL oxidation. Neutrophil O2−generating capacity was assessed by a lucigenin‐based chemiluminescent assay of NADPH oxidase activity. Body composition was assessed using bioelectrical impedance analysis.

results Compared to controls, GHD subjects had higher LDL cholesterol (4·0 ± 0·8 vs. 3·5 ± 0·9 mmol/l, P < 0·01) and higher triglyceride concentrations (2·3 ± 1·5 vs. 1·1 ± 0·7 mmol/l, P < 0·001) but lower HDL cholesterol (1·1 ± 0·3 mmol/l vs. 1·4 ± 0·4 mmol/l, P < 0·01), lower levels of HPOs (0·72 ± 0·35 vs. 0·92 ± 0·20 µm, P < 0·01) and lower basal (2·5 ± 1·5 vs. 4·5 ± 2·3 mV/5 × 105 neutrophils, P < 0·01) and peak post‐activation levels (23·2 ± 11·1 vs. 34·4 ± 15·6 mV/5 × 105 neutrophils, P < 0·01) of neutrophil O2− generation. GH replacement resulted in an increase in HPOs from 0·70 ± 0·39 to 0·86 ± 0·19 µm (P < 0·05), although there was no change in the lag time of LDL oxidation. Neutrophil O2− generating capacity was enhanced with a rise in basal O2− generation from 2·8 ± 1·4 to 5·4 ± 4·6 mV/5 × 105 neutrophils (P < 0·05) and in peak post‐activation O2− generation from 21·9 ± 9·5 to 35·8 ± 21·7 mV/5 × 105 neutrophils (P < 0·05). LDL cholesterol was reduced from 4·1 ± 0·8 mmol/l to 3·5 ± 0·8 mmol/l (P < 0·01). No significant changes in measured parameters occurred in the placebo group.

conclusions Adult GHD is associated with reduced lipid peroxidation and impaired neutrophil O2− generating capacity, both of which are reversible with GH replacement. Our data suggest that: (i) that oxidative stress is not a major feature of the pro‐atherogenic state in hypopituitary adults with GHD and (ii) a role for GH in modulating neutrophil function and leucocyte–lipoprotein interactions.
Anaplastic pseudothyroiditis
Authors: Basaria Shehzad , Udelsman Robert , Tejedor‐Sojo Javier , Westra William H. , Krasner Alan S.
Published: March 2003

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumours. It generally presents as a rapidly enlarging thyroid mass and produces local symptoms associated with mass effect. One of the very rare presentations of ATC is thyrotoxicosis. We report a patient with ATC whose course was complicated by severe thyrotoxicosis. His symptoms were controlled with beta‐blockers. Two weeks into hospitalization, the patient became hypothyroid. Histopathology showed destruction of the normal thyroid follicles by the invasion of the tumour. As this form of thyrotoxicosis resembles various thyroiditides, we hereby refer this condition as ‘anaplastic pseudothyroiditis’.
A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty
Authors: Arroyo Armando , Pernasetti Flavia , Vasilyev Vyacheslav V. , Amato Paula , Yen Samuel S. C. , Mellon Pamela L.
Published: March 2003

We report a 28‐year‐old‐female who presented with primary amenorrhoea, absence of puberty, obesity and normal stature. The subject was clearly short as a child, with a height more than 2 SD below normal until the age of 15 years. The pubertal growth spurt failed to develop. She continued growing at a prepubertal rate until growth ceased at the age of 20 years, reaching her final adult height of 157 cm (SDS −0·86) without hormonal treatment. A combined pituitary hormone stimulation test of anterior pituitary function showed deficiencies of GH, LH and FSH, and low normal serum levels of TSH and PRL. Magnetic resonance imaging revealed a hypoplastic pituitary with markedly reduced pituitary height. In addition, a whole body dual energy X‐ray absorptiometry scan showed high levels of body fat (54%). Combined pituitary hormone deficiencies with a hypoplastic pituitary suggested the diagnosis of a Prophet of Pit‐1 (PROP1) gene mutation. Normal stature in this case, however, confounded this diagnosis. Sequencing of PROP1 revealed homozygosity for a single base‐pair substitution (C to T), resulting in the replacement of an Arg by a Cys at codon 120 (R120C) in the third helix of the homeodomain of the Prop‐1 protein. To our knowledge, this is the first report of a patient with a mutation in the PROP1 gene that attained normal height without hormonal treatment, indicating a new variability in the PROP1 phenotype, with important implications for the diagnosis of these patients. We suggest that this can be explained by (i) the presence of low levels of GH in the circulation during childhood and adolescence; (ii) the lack of circulating oestrogen delaying epiphyseal fusion, resulting in growth beyond the period of normal growth; and (iii) fusion of the epiphyseal plates, possibly as a result of circulating oestrogens originating from peripheral conversion of androgens by adipose tissue.
Timing of onset of growth hormone deficiency is a major influence on insulin‐like growth factor I status in adult life
Authors: Lissett C. A. , Murray R. D. , Shalet S. M.
Published: March 2003

objective Several reports have suggested that IGF‐I levels in patients with childhood‐onset (CO) GH deficiency are lower than those observed in patients with adult‐onset (AO) GH deficiency. However, these reports are unsatisfactory as there are several differences between the cohorts studied other than the timing of onset of GH deficiency; in particular, the patients were not matched for equal severity of GH deficiency. We have pursued this question further by examining the IGF‐I standard deviation score (SDS) in patients with CO and AO GH deficiency, with equal degrees of severity of GH deficiency, as defined by the peak GH response to the insulin tolerance test (ITT).

patients and measurements IGF‐I SDS were compared in 146 non acromegalic patients (69 male), aged 15·7–76·6 years (median 33·4 years), bone mass index (BMI) 27·8 ± 5·8 kg/m2, with severe GH deficiency (peak GH response < 9 mU/l to insulin‐induced hypoglycaemia). Patients were subdivided by timing of onset of GH deficiency and the peak GH response to the ITT (GH response ≤ 1 mU/l, group 1; > 1–3 mU/l, group 2; > 3–6 mU/l, group 3; > 6–8·9 mU/l, group 4).

results The IGF‐I SDS (mean value ± SD) in the CO group (n = 63) as a whole was significantly lower than that found in the AO group (n = 83) (−3·7 ± 2·8 vs.−1·55 ± 2·2, respectively; P < 0·0001). Despite this, there was no significant difference in the peak GH response to an ITT between the two cohorts (2·8 ± 2·3 mU/l in the AO cohort and 2·6 ± 2·2 mU/l in the CO cohort; P = 0·5). When the cohorts were subdivided by severity of GH deficiency, there remained a significant difference in IGF‐I SDS in groups 1 (P < 0·0001), 2 (P = 0·05) and 3 (P < 0·05), but there was no significant difference between the AO and CO cohorts in group 4. The peak GH response to an ITT was similar in the AO and CO cohorts in all groups (P = 0·8, 0·8, 0·9 and 0·3 in groups 1–4, respectively).

Although increasing severity of hypopituitarism was associated with a decline in IGF‐I SDS in the CO cohort (P < 0·01), this was not the case in the AO cohort (P = 0·3).

conclusion These data support the hypothesis that there is an innate difference between adult patients with either CO or AO GH deficiency that cannot be explained solely by variation in the severity of GH deficiency. A possible explanation is that childhood GH deficiency programmes the subsequent relationship between GH and IGF‐I in adult life or that the body composition changes, which are more severe in AO GH deficiency, influence IGF‐I status.
Suppression of puberty with long‐acting goserelin (Zoladex‐LA): effect on gonadotrophin response to GnRH in the first treatment cycle
Authors: Trueman Julie A. , Tillmann Vallo , Cusick Colin F. , Foster Peter , Patel Leena , Hall Catherine M. , Price David A. , Clayton Peter E.
Published: March 2003

background and objectives Depot GnRH analogues are widely used in the treatment of precocious puberty, or suppression of relatively early puberty where growth or psychosocial well‐being may be compromised. One example is Zoladex (Z goserelin 3·6 mg), which can be given every 4 weeks. This injection frequency may not always achieve adequate suppression of pubertal signs. A long‐acting form, Zoladex‐LA 10·8 mg, has now been introduced with a potential duration of action of 12 weeks. In order to assess the efficacy of Zoladex‐LA in gonadotrophin suppression we have measured LH and FSH responses to GnRH at diagnosis and 8 and 12 weeks after injection in a group of children treated with Zoladex‐LA for central precocious or early puberty.

methods Forty‐nine children (40 girls) with clinical evidence of central precocious puberty (CPP) or early puberty (EP) were started on Zoladex‐LA, either de novo (n = 29) or on changing from Zoladex. Ages at diagnosis ranged from 1·7 to 10·6 years (median 7·8 years). Twenty‐three had a structural cause with abnormality on magnetic resonance/computerized tomography (MR/CT) head scan, nine had a syndrome or nonspecific brain injury, and in 17 the cause was idiopathic.

results At diagnosis, in the de novo group, median peak LH was 13·6 IU/l and median peak FSH was 12·0 IU/l. By 12 weeks gonadotrophins were suppressed to 0·9 and 0·8 IU/l, respectively. In the previously treated group, median peak LH at diagnosis was 12·8 IU/l and median peak FSH was 15·0 IU/l with suppression to 0·8 and 1·1 IU/l, respectively, at 12 weeks. In the latter group peak FSH was higher than peak LH at both 8 and 12 weeks (P < 0·05) and there was a significant rise in peak LH (P < 0·05) and FSH (P = 0·01) between 8 and 12 weeks. There was no correlation between age at diagnosis and peak LH or FSH at 8 or 12 weeks. Nevertheless, individual patients in both groups showed evidence of incomplete gonadotrophin suppression at 12 weeks.

conclusion Zoladex‐LA induces a significant reduction in gonadotrophins over 12 weeks. However, there are individuals, particularly those previously on Zoladex, in whom gonadotrophin suppression is waning by 12 weeks. As found with Zoladex, some children with precocious puberty treated with Zoladex‐LA may require increased injection frequency, although correlation with clinical evidence of suppression needs to be studied further.
Growth hormone (GH) replacement therapy in GH‐deficient women during pregnancy
Authors: Wirén Lena , Boguszewski Cesar Luiz , Johannsson Gudmundur
Published: March 2003

objective The present recommendation is to discontinue GH replacement therapy in hypopituitary women, as they become pregnant. We report our experience of managing GH deficiency with GH replacement therapy in pregnant hypopituitary women.

patients and measurements Eight hypopituitary women, median age 30·5 years (range 20–39 years), were followed prospectively during 12 distinct pregnancies. Six women were receiving replacement therapy for other pituitary hormone deficiencies and five pregnancies were achieved with ovulation induction therapy. GH replacement therapy was maintained at the same pregestational dose during the first trimester, with a gradual decrease of the dose during the second trimester and discontinuing the treatment at the beginning of the third trimester. Serum IGF‐1 levels were measured in four selected pregnancies at three different points, one in each trimester of gestation.

results Seven pregnancies resulted in normal vaginal deliveries and five had programmed Caesarian sections. The median gestation age at time of delivery was 40 weeks (range 33–42 weeks). Newborns had a median birthweight SD score of −0·37 (range −1·93 to 1·21) and a median birthlength SD score of 0·07 (range −2·73 to 1·53). No congenital malformations were observed. Three women were able to breastfeed their babies. Before gestation, the median daily dose of GH was 0·5 mg (range 0·3–0·8 mg) and the median serum IGF‐1 was 37·5 nmol/l (range 7·6–54·5 nmol/l). IGF‐1 levels were fairly constant in the first and second trimesters of gestation, showing an increment during the last trimester, when GH treatment was discontinued.

conclusion The GH replacement regimen presented for pregnant women with GH deficiency was safe. No major side‐effects and no negative influences on maternal and fetal outcome were observed.
Ultrasonography for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism: comparison with 99mtechnetium sestamibi scintigraphy
Authors: Haber Richard S. , Kim Chun K. , Inabnet William B.
Published: March 2003

objective To determine the utility of ultrasonography for the preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism, and to compare this method with 99mtechnetium sestamibi scintigraphy.

design The results of ultrasonography for localization of enlarged parathyroid glands were determined in 120 consecutive patients with primary hyperparathyroidism and compared with findings at surgery (n = 86) and with the results of 99mtechnetium sestamibi scintigraphy (n = 99).

patients All patients had biochemically documented primary hyperparathyroidism based on elevated serum calcium and ‘intact’ parathyroid hormone measured by immunoassay. Patients with prior parathyroid surgery or secondary hyperparathyroidism were excluded.

measurements High‐resolution ultrasonography was performed by a single observer. 99mTechnetium sestamibi scintigraphy was performed using early and delayed (2‐h) views, and correlated with simultaneous thyroidal 123I uptake in most patients.

results Ultrasonography detected putative enlarged parathyroid glands in 92 of 120 unselected patients (77%). It correctly predicted surgical findings in 64 of 86 patients undergoing surgery (74%), including 61 of 72 patients with solitary eutopic parathyroid adenomas (84%), but only two of eight patients with solitary ectopic adenomas, and only one of six patients with multigland parathyroid disease.

Sestamibi scintigraphy was positive in 87 of 99 unselected patients (88%), a higher proportion than ultrasonography (P < 0·05), reflecting superior sensitivity for the detection of ectopic parathyroid adenomas. For 74 patients undergoing parathyroid surgery who underwent both imaging tests there was no statistically significant difference between ultrasonography and sestamibi scintigraphy in ability to correctly predict surgical findings (74%vs. 82%, respectively) or in positive predictive value (93%vs. 90%, respectively). However, sestamibi scintigraphy was clearly more sensitive for ectopic parathyroid adenomas, providing correct localization in 8/8 cases. When one test was negative, testing with the second method was usually positive, improving the likelihood of a positive result to 98% when both tests were employed.

conclusions Ultrasonography can be a sensitive and accurate method for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism, comparable in overall utility to sestamibi scintigraphy. These results suggest that a strategy of initial testing with one or the other method, followed by the alternate imaging test if the first test is negative, would provide correct parathyroid imaging in most patients without prior parathyroid surgery.
In vitro effect of human recombinant leptin and expression of leptin receptors on growth hormone‐secreting human pituitary adenomas
Authors: Giusti Massimo , Bocca Liliana , Florio Tullio , Corsaro Alessandro , Spaziante Renato , Schettini Gennaro , Minuto Francesco
Published: March 2003

objective and study design Leptin is a circulating hormone secreted by adipose tissue and a few other tissues. It has recently been demonstrated that leptin and leptin receptors are expressed in normal and adenomatous pituitary cells. The aim of this study was to investigate the effect of recombinant human leptin on GH release from adenomatous GH‐secreting cells in culture. Specimens were obtained from 10 patients with acromegaly who had undergone selective transsphenoidal adenomectomy. Cells (2 × 105/well) preincubated for 24 h with leptin (10−10−10−8 m) or control medium were exposed to GHRH for 2 h. The GH released into the medium was measured before and after GHRH incubation. The expression of leptin receptor isoforms was evaluated by reverse‐transcriptase polymerase chain reaction (RT‐PCR) in cells obtained from five adenomas.

results After the first incubation, there was a slight dose‐dependent leptin‐induced decrease in GH released into the medium. A significant increase in GH release after GHRH was noted from cells previously exposed to leptin in comparison with cells incubated with medium alone. Expression of leptin receptors was found in two out of five GH‐secreting adenomas evaluated.

conclusions Our data confirm that some, but not all, GH‐secreting adenomas express leptin receptors. Leptin seems to exert both a slight inhibitory effect on spontaneous GH secretion and a stimulatory effect on GHRH‐stimulated GH secretion from GH‐secreting adenomatous tissue.
Suprasellar germ cell tumours: specific problems and the evolution of optimal management with a combined chemoradiotherapy regimen
Authors: Janmohamed S. , Grossman A. B. , Metcalfe K. , Lowe D. G. , Wood D. F. , Chew S. L. , Monson J. P. , Besser G. M. , Plowman P. N.
Published: March 2003

objective Suprasellar germ cell tumours are rare, and there are few series of patients outlining the problems in diagnosis and management, and providing clear guidelines for optimal therapy. We have therefore reviewed our own series of 11 such patients who were managed in a joint endocrinology/clinical oncology setting.

patients and design A retrospective case review assessment of all patients seen within a given time. Clinical, biochemical and radiological findings were reviewed, the types of therapy administered noted, and the responses to treatment analysed.

results In the years 1977–2001, 11 patients with suprasellar (SS) germ cell tumours (GCT) were seen (germinomatous : nongerminomatous = 8 : 3). SSGCT had an approximately equal sex incidence (M : F, 6 : 5), in contrast to pineal tumours, the commonest site of origin of intracranial GCT and which occur predominantly in men. The median age at presentation was 20 years (range 6–49 years) with a median duration of symptoms before diagnosis of 17 months (range 1–35 months). Polyuria was the commonest presenting symptom (10 patients). Diabetes insipidus occurred in all patients, as did partial or complete anterior pituitary failure. Visual failure was present in 55% of cases. Anorexia, weight loss and disturbed thirst sensation were also common. Positron emission tomography scanning was occasionally useful in the evaluation of suprasellar tumours/pituitary stalk lesions deemed too risky to biopsy. A ‘central nervous system‐friendly’ chemoradiotherapy regimen comprising vincristine, etoposide and carboplatin and differential daily dose irradiation, usually administered using a partial transmission block technique, produced a 5‐year survival of 100% with low morbidity. Treatment did not correct previously abnormal endocrine function although it did improve vision in three of six patients.

conclusions We therefore emphasize the use of techniques other than biopsy in the diagnosis of these patients, note the problems in the management of their fluid control, and highlight the favourable response to a combined chemotherapy‐radiotherapy protocol.
Serum leptin and CD4+ T lymphocytes in HIV+ children during highly active antiretroviral therapy
Authors: Matarese G. , Castelli‐Gattinara G. , Cancrini C. , Bernardi S. , Romiti M. L. , Savarese C. , Di Giacomo A. , Rossi P. , Racioppi L.
Published: March 2003

objective Because leptin, the adipocyte‐derived hormone, affects thymocyte survival, proliferation of naïve T lymphocytes and the production of proinflammatory cytokines, we aimed to investigate the role of this molecule in immunoreconstitution during highly active antiretroviral therapy (HAART).

design Prospective longitudinal cohort study. A series of 20 HIV+ children were studied. The subjects were grouped by their increase in serum leptin levels after HAART.

methods All participants were weight‐stable, free of endocrine disorders and opportunistic infections and equally distributed for sex (males, n= 10; females, n= 10). Body mass index (BMI), serum lipids, leptin, CD4+ T cells and HIV‐1 RNA were measured before initiation of HAART and after a 2‐year follow‐up.

results Serum leptin concentration positively correlated with CD4+ lymphocyte number before treatment. HAART significantly reduced viraemia and increased serum levels of lipids in all patients, whereas a significant increase in CD4+ cells and serum leptin was observed in the majority of patients. Notably, in children where HAART was not effective in increasing CD4+ lymphocyte counts, serum leptin did not increase.

conclusion To our knowledge, these findings reveal for the first time a novel link among CD4+ T lymphocytes, serum leptin and highly active anteretroviral theraphy.
Glucocorticoid receptor gene polymorphisms in ACTH‐secreting pituitary tumours
Authors: Antonini S. R. R. , Latronico A. C. , Elias L. L. K. , Cukiert A. , Machado H. R. , Liberman B. , Mendonca B. B. , Moreira A. C. , Castro M.
Published: March 2003

objective The inhibitory action of glucocorticoids on the hypothalamic‐pituitary axis is disrupted in ACTH‐secreting pituitary tumours. The molecular events leading to the development of these tumours and their relative resistance to glucocorticoids are unknown. We investigated the presence of mutations and polymorphisms of the glucocorticoid receptor (GR) gene in corticotropinoma and their possible relationship with the tissue‐specific resistance to glucocorticoids.

design and methods DNA or RNA was extracted from 18 corticotropinomas and the GR gene was amplified by the polymerase chain reaction (PCR) or reverse transcriptase‐PCR followed by automated direct sequencing.

results We did not identify any mutation in the coding region and the exon–intron boundary regions of the GR gene. The polymorphism AAT > AGT at codon 363 (N363S) was found in 17% and the polymorphism AAT > AAC at codon 766 (N766N) in 11% of tumours, both in heterozygous state. The polymorphisms at codons 22 and 23, at introns 3 and 4, and at codon 618, previously described in normal population, were not observed.

conclusions Our results show that GR gene mutations are rare and unlikely to contribute to the glucocorticoid resistance observed in corticotropinomas. Polymorphisms in the GR gene might confer a selective advantage to tumorigenesis in corticotropinoma. However, there was no relationship between GR gene polymorphism and clinical presentation, tumour size or surgery outcome, suggesting that tumour growth may not be directly related to alterations of the GR gene structure.