bluuebunny/crossref_metadata_2025 huggingface dataset:
The negative association between serum free testosterone and leptin is dependent on insulin‐like growth factor‐binding protein 1 in healthy young and middle‐aged men
Authors: Marie Erturth Eva , Ahrén Bo
Published: March 2003

OBJECTIVE Previous studies have shown that serum levels of testosterone correlate negatively with leptin and positively with insulin‐like growth factor binding protein 1 (IGFBP‐1). The present study examined whether these associations are linked. DESIGN AND PATIENTS The association between serum levels of IGFBP‐1, free testosterone and insulin on one hand and leptin on the other hand were investigated in 38 healthy men with a medlan age of 48 years (range 23‐62 years). RESULTS Univariate analyses revealed that serum levels of leptin correlated negatively with serum free testosterone (r=−0.42, P=0.008) and with serum IGFBP‐1 (r=‐0.45, P= 0.005) and positively with body mass index (BMI; r=0.46, P=0.003) and serum insulin (r=0.45, P=0.004). Serum free testosterone correlated with IGFBP‐1 (r=0.42, P=0.008) but not with serum insulin (r=‐0.08, ns). The correlations between leptin and free testosterone and between leptin and IGFBP‐1 remained significant after adjustement for the influences of BMI and insulin. Forward stepwise multiple regression when BMI, insulin, testosterone and IGFBP‐1 were entered in a model as independent variables and leptin as the dependent variable showed that BMI and IGFBP‐1 were independent predictors of circulating leptin. These two parameters yielded an r2 of 0.38, thereby together explaining approximately 40% of serum leptin. CONCLUSION Serum levels of free testosterone and IGFBP‐1 correlate negatively with serum leptin in healthy nonobese men but this influence is dependent on the influence of IGFBP‐1. The study therefore suggests an important impact of IGFBP‐1 on the regulation of circulating leptin in young and middle‐aged men.
Abnormal LH pulsatility in women with hyperprolactinaemic amenorrhoea normalizes after bromocriptine treatment: deconvolution‐based assessment
Authors: Sartorio  , Pizzocaro  , Liberati  , De Nicolao  , Veldhuis  , Faglia
Published: March 2003

OBJECTIVE

The present study examines the LH secretory process in hyperprolactinaemic women before, during and after bromocriptine therapy, using restrictive clinical selection criteria as well as improved methodological tools.

PATIENTS AND DESIGN

Six women (aged 20–40 years) with microprolactinomas (mean ± SE prolactin, PRL: 2478 ± 427 mU/l, range: 1370–3800 mU/l) and four age‐ and sex‐matched healthy controls were admitted to the study. After an overnight fast, all patients and controls had blood samples withdrawn at 10 minute intervals for 6 h (during saline infusion) from 0800 h to 1400 h to determine serum LH and PRL concentrations. After baseline evaluation, patients were treated with bromocriptine, which was started at a daily dose of 1.25 mg for 7 days; the dose was then increased to 2.5 mg daily for the next 7 days and subsequently to 2.5 mg twice daily. PRL levels were evaluated at weekly intervals after the beginning of bromocriptine therapy for the duration of the study. The 6 h pulsatility study was repeated on four patients during treatment at a time when PRL levels were decreased, although not normalized (PRL range: 450–1350 mU/l) and, on four patients, with the attainment of normal serum PRL levels (PRL < 450 mU/l) in the early follicular phase of the menstrual cycle (days 2–5). The LH instantaneous secretion rate was reconstructed by a nonparametric deconvolution method. In addition to pulse analysis made using the program DETECT, the evaluation of the secretion rate yielded the pulse frequency as well as the pulse amplitude distribution.

RESULTS

Each time series was submitted to deconvolution analysis using a nonparametric method in order to estimate the instantaneous secretion rate (ISR). Hyperprolactinaemic patients had very few high‐amplitude LH pulses above 0.2 IU/(l minutes) before treatment (average frequency: 0.83 ± 0.40 pulses/6 h) and at the intermediate evaluation (0.25 ± 0.25 pulses/6 h). In both cases, the pulse frequency was significantly lower than in controls (P < 0.05 and P < 0.01, respectively). When PRL was normalized, the number of high‐amplitude LH pulses (4.25 ± 1.03 pulses/6 h), became statistically different from the pulse number before (P < 0.01) and during (P < 0.01) therapy; in particular the pulse frequency after therapy rose to a level not statistically different from that in controls.

CONCLUSION

The present study shows the presence of reduced LH pulsatility in hyperprolactinaemic women that recovers completely to within the physiological distribution when PRL levels are normalized by bromocriptine therapy.
Loss of heterozygosity in sporadic parathyroid tumours: involvement of chromosome 1 and the MEN1 gene locus in 11q13.
Authors: Dwight Trisha , Twigg Stephen , Delbridge Leigh , Wong Fung‐Ki , Farnebo Filip , Richardson Anne Louise , Nelson Anne , Zedenius Jan , Philips Jeanette , Larsson Catharina , Teh Bin Tean , Robinson Bruce
Published: March 2003

OBJECTIVE

Hyperparathyroidism (HPT) is a common endocrine disorder. Several loci of genetic interest have been identified in parathyroid tumours, including the MEN1 gene locus at 11q13; the HPT‐JT region at 1q21‐q32; and a putative tumour suppressor gene on 1p. We analysed these intervals, which harbour known genes or putative loci associated with familial hyperparathyroidism, in order to clarify the involvement of the respective regions in parathyroid tumourigenesis.

DESIGN

We performed loss of heterozygosity (LOH) studies on 33 sporadic parathyroid tumours using a PCR based technique. A total of 22 microsatellite markers were used to analyse loci at 11q13, 1q21‐q32 and 1p. Ten markers located distal on 1p, eight markers encompassed the HPT‐JT region at 1q21‐q32 and four markers surrounded the MEN1 gene locus at 11q13. MEN1 mutations were screened for using Single Strand Conformation Polymorphism analysis (SSCP) and automated sequencing of SSCP variants.

PATIENTS

Thirty‐three parathyroid glands and the corresponding blood samples were obtained from 33 patients (26 females and seven males) who underwent parathyroidectomy for primary hyperparathyroidism.

RESULTS

Loss of heterozygosity was detected in 13 of 33 (39%) cases at 11q13, 6 of 33 (18%) cases at 1p, and in three of 33 (9%) cases at 1q (in conjunction with 1p loss). Only one of the 18 tumours in which LOH was detected, showed LOH at both chromosome 1 and chromosome 11. Additionally, those tumours found to exhibit LOH at 11q13 were screened for MEN1 mutations using single strand conformation polymorphism analysis (SSCP) and automated sequencing. Nine novel somatic mutations were found on the remaining allele in 13 (69%) tumours.

CONCLUSIONS

This study consolidates the role of multiple loci in the pathogenesis of sporadic parathyroid tumours. The results indicate that there are at least two genetic loci involved in sporadic parathyroid tumourigenesis on chromosome 1, one of which has been linked to the distinct familial parathyroid condition, hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome. The high frequency of loss of heterozygosity at 1p suggests the presence of a tumour suppressor at this locus.
A polymorphism of the 5′ flanking region of tumour necrosis factor α gene is associated with thyroid‐associated ophthalmopathy in Japanese
Authors: Kamizono Shintaro , Hiromatsu Yuji , Seki Naoko , Bednarczuk Tomasz , Matsumoto Hajime , Kimura Akinori , Itoh Kyogo
Published: March 2003

OBJECTIVE

We have studied the polymorphism of the 5′ flanking region of the tumour necrosis factor (TNF)‐α gene in order to better understand the genetic background of autoimmune thyroid disorders and thyroid‐associated ophthalmopathy.

PATIENTS AND METHODS

We studied the polymorphism of the 5′ flanking region of the TNF‐α gene at positions − 1031 (T to C change, termed as − 1031C), − 863 (C to A, − 863 A), − 857 (C to T, − 857T), − 308 (G to A, − 308 A) and − 238 (G to A, − 238 A) in Japanese patients with Graves' disease [n = 173, 62 of whom had associated ophthalmopathy (American Thyroid Association (ATA) class III or greater)] and healthy control subjects (n = 575), using a polymerase chain reaction sequence‐specific oligonucleotide probe method.

RESULTS

The allele frequency of − 857T in the Graves' disease patients (22.5% vs. 17.7%, OR  = 1.35, P  = 0.045, corrected P  = 0.23) was slightly greater than in the Japanese healthy subjects, respectively. However, the difference was not statistically significant. In Graves' disease patients with evident ophthalmopathy (ATA class III or greater), the allele frequencies of − 1031C and − 863 A were significantly greater than those with no or mild ophthalmopathy (ATA class 0–II) (31.5% vs. 13.5%, OR =2.94, P < 0.0001, corrected P < 0.0005; 23.4% vs. 11.7%, OR =2.30, P  = 0.0044, corrected P  = 0.022, respectively) and in control subjects. The strength of the association of the polymorphism − 1031C increased with the severity of ophthalmopathy, with odds ratios of 2.36 for ATA class III, and 5.43 for ATA class IV–VI, respectively, compared with Graves' disease with no or mild ophthalmopathy (ATA class 0–II). Although the phenotype frequency of DRB1*0901 was not different among Graves' disease patients with or without ophthalmopathy and control subjects, the phenotype frequency of DRB1*0901(−)/−1031C(+) was significantly increased in Graves' disease patients with ophthalmopathy compared to those with no or mild ophthalmopathy (OR = 4.91, P  = 0.0005) or control subjects (OR = 4.59, P < 0.0001).

CONCLUSIONS

These results suggest that the − 1031C or − 863 A alleles, or a gene in linkage disequilibrium with the TNF‐α gene, predispose to the development of ophthalmopathy in Japanese patients with Graves' disease.
The somatotrophic system in patients with dilated cardiomyopathy: Relation of insulin‐like growth factor‐1 and its alterations during growth hormone therapy to cardiac function
Authors: Osterziel Karl Josef , Ranke Michael B. , Strohm Oliver , Dietz Rainer
Published: March 2003

OBJECTIVE

Treatment with human recombinant growth hormone has yielded conflicting results in patients with congestive heart failure. In addition, growth hormone resistance has been reported in severe heart failure. Therefore, the purpose of this study was to evaluate the somatotrophic axis and effects of growth hormone on haemodynamics in patients with heart failure due to dilated cardiomyopathy.

DESIGN

Randomized, double‐blind, placebo‐controlled trial.

PATIENTS

Fifty clinically‐stable patients with moderate heart failure (mean left ventricular ejection fraction = 26 ± 2%) due to dilated cardiomyopthy were examined.

MEASUREMENTS

Patients were randomly assigned to treatment with placebo or 2 IU/d sc human recombinant growth hormone for a mean of 14 weeks. Cardiac size and function were evaluated by magnetic resonance imaging. Central haemodynamics were obtained by right heart catheterization. Measurements of plasma noradrenaline, serum insulin‐like growth factor‐1, and insulin‐like growth factor binding protein‐3 were performed by standard assays at baseline and at the end of the treatment period.

RESULTS

The severity of heart failure as determined by stroke volume, left ventricular end diastolic diameter and plasma noradrenaline concentrations correlated significantly to baseline serum insulin‐like growth factor‐1 levels (each P < 0.05). The growth hormone‐induced increase of insulin‐like growth factor‐1 predicted the changes in ejection fraction (P < 0.05). A significant increase in ejection fraction of 7% was observed in patients whose insulin‐like growth factor‐1 increased by more than the median increase in comparison to the patients with an increase below the median (+ 4.0 ± 2.3% vs. − 3.0 ± 1.8%; P = 0.03).

CONCLUSIONS

Serum levels of insulin‐like growth factor‐1, reflecting growth hormone secretion, are diminished in relation to the severity of heart failure in patients with dilated cardiomyopathy. Growth hormone induced increases of insulin‐like growth factor–1 of more than 77 ng/l caused significant improvement of ejection fraction.
Cranial radiotherapy of childhood brain tumours: Growth hormone deficiency and its relation to the biological effective dose of irradiation in a large population based study
Authors: Schmiegelow  , Lassen  , Poulsen  , Feldt‐Rasmussen  , Schmiegelow  , Hertz  , Müller
Published: March 2003

OBJECTIVE

The study was to determine the incidence of GH deficiency (GHD) following cranial radiotherapy (RT) for a childhood brain tumour in a large population based study and analyse the biological effective dose (BED) to the hypothalamus/pituitary (HP) region as a risk factor.

DESIGN

BED was assessed by use of the linear‐quadratic (LQ) model, which gives a means of expressing the biological effect of various treatment schedules in a uniform way. In patients aged ≥ 18 years (n = 53) GH status was assessed by an insulin‐tolerance test (ITT) (n = 34), however, in patients with seizure disorders (n = 19), and in 20 children aged < 18 years GH status was assessed by an arginine test. Cut‐off levels for GHD, indicating GH substitution, were defined by a peak GH response of < 9 mU/l and < 15 mU/l for patients ≥ 18 and < 18 years, respectively.

PATIENTS

Ninety‐one children aged < 15 years eligible for the study, diagnosed between 1970 and 1997 in the Eastern part of Denmark, the Faroe Islands and Greenland, with a primary brain tumour not directly involving the HP axis. 84% (n = 76) agreed to participate. Three patients were excluded due to hypothyroidism detected at time of testing.

MEASUREMENTS

Serum GH and levels of serum insulin‐like growth factor‐I (s‐IGF‐I) and serum insulin‐like growth factor binding protein‐3 (s‐IGFBP‐3) were measured. BED was assessed to the HP region.

RESULTS

The median age at the time of RT was 8.7 years (range: 0.8–14.9 years) and the median time of follow‐up was 15 years (range: 2–28 years). Fifty‐eight patients (80%) had GHD and they had received a median BED of 77.5 Gy to the HP region, whereas the median BED was 54.5 Gy for 15 patients without GHD (P = 0.002). Peak GH and BED were correlated (rs = −0.53, P < 0001). Median IGF‐I SDS and IGFBP‐3 SDS were −2.5 (−5.2–0.7 SDS) and −1.7 (−5.8–0.9 SDS), respectively, and IGF‐I SDS was correlated to peak GH (rs = 0.45, P < 0.001). Peak GH and length of follow‐up were related (rs = −0.28, P = 0.018). Stepwise backward multiple linear regression analysis showed that the best‐fit model to predict the peak GH release following ITT/arginine stimulation included BED (P < 0.0001) and length of follow‐up (P = 0.05).

CONCLUSIONS

The data of this study suggest that the majority of long‐term survivors of brain tumours develop GH deficiency following radiotherapy in childhood and that the adverse effects of radiotherapy may be directly related to the biologically effective dose. With longer follow‐up fewer patients might respond normally to GH stimulation tests.
Serum levels of free insulin‐like growth factor (IGF)‐I and IGF‐binding protein‐1 in prepubertal children with idiopathic short stature
Authors: Kamoda Tomohiro , Saitoh Hisako , Hirano Takeki , Matsui Akira
Published: March 2003

The study was performed to evaluate the relationships among serum free and total insulin‐like growth factor (IGF)‐I, IGF‐binding protein‐1 (IGFBP‐1), IGFBP‐3, and insulin concentrations in prepubertal children with idiopathic short stature (ISS).

Eighteen children with ISS and 15 age‐matched controls were included in the study. All short children had a height standard deviation score of more than 2 below the mean, and maximum stimulated GH levels greater than 10 µg/l after two standard provocation tests.

The serum levels of free IGF‐I were significantly lower in short children (1·6 ± 0·3 µg/l) than in the controls (2·8 ± 0·6 µg/l, P < 0·05), while total IGF‐I levels were slightly, but not significantly, lower in short children than in controls. The serum levels of IGFBP‐1 were significantly higher in the ISS group (124·6 ± 5·6 µg/l) than in controls (80·0 ± 8·7 µg/l, P < 0·0001). The fasting insulin and IGFBP‐3 levels were similar in both groups. A stepwise regression analysis for all subjects revealed that IGFBP‐1 is the only independent predictor of log free IGF‐I (R2 = 0·23, P < 0·01).

The present study shows that the serum levels of free IGF‐1 are significantly lower and insulin‐like growth factor‐binding protein‐1 levels are higher in prepubertal children with idiopathic short stature, as compared with age‐matched controls. The high IGFBP‐1 may contribute to growth retardation in a subgroup of idiopathic short stature through a decrease in free IGF‐1.
Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study
Authors: Papathanassoglou Elizabeth D. E. , Moynihan Jan A. , Ackerman Michael H. , Mantzoros Christos S.
Published: March 2003

OBJECTIVE

Hypercatabolism and immune dysfunction are closely associated with the development of systemic inflammatory response–multiple organ dysfunction (SIRS/MODS) in critical illness. It remains unclear however, whether leptin, an adipocyte‐derived hormone whose levels are influenced by several cytokines and which regulates immune function, food‐intake and energy expenditure is independently related to the development of and/or severity and mortality from SIRS/MODS.

DESIGN and PATIENTS

To assess the role of leptin in SIRS/MODS we performed a matched case control and a longitudinal study (14 days) in 35 critically ill patients with SIRS/MODS and 35 matched controls.

RESULTS

Baseline leptin levels were positively associated with body mass index (BMI) and TNF‐α (P < 0·01) in patients and with IGF‐1 and IL‐6 levels (P < 0·05) in controls. Furthermore, leptin levels exhibited a progressive increase from the first to the last day of the study and although baseline levels were not different, peak leptin levels as well as leptin levels on the last day of the study were significantly higher in cases than in controls (P < 0·05). TNF‐α levels, IL‐6 and cortisol levels were also higher, whereas IGF‐1 levels were lower in cases (P < 0·05). To assess whether leptin levels are independently associated with SIRS/MODS we performed multivariate logistic regression analysis which revealed that leptin up‐regulation in cases is mediated by elevated TNF‐α and cortisol levels. Finally, there was no independent association between leptin and survival in this group of critically ill patients.

CONCLUSION

We conclude that cytokines and cortisol upregulate leptin levels, which may contribute to the development of the hypercatabolism, wasting and immune dysfunction but leptin levels are not independently associated with severity or mortality of patients with systemic inflammatory response–multiple organ dysfunction .
A critical examination of adrenal tuberculosis and a 28‐year autopsy experience of active tuberculosis
Authors: Lam King Yin , Lo Chung Yau
Published: March 2003

OBJECTIVE Tuberculosis is potentially fatal and adrenal gland involvement is uncommonly reported. The aims of the current study were to define the characteristics of tuberculosis in hospitalized patients and to analyse the features of adrenal tuberculosis.

DESIGN Retrospective analysis of autopsies and adrenalectomies.

Patients 13 762 patients (13492 at autopsies and 270 at adrenalectomy).

MEASUREMENTS The presence of active tuberculosis, the predisposing factors, the pathological features and organs of involvement were examined.

RESULTS Active tuberculosis was present in 871 patients (6·5% of all 13492 autopsies). It was first diagnosed in 70% of these patients during autopsy. Cancers and a history of recent major operations were the 2 main concomitant factors in the patients with tuberculosis. Extra‐pulmonary tuberculosis was seen in 261 patients (30%). The five most common extra‐pulmonary sites of tuberculosis were the liver, spleen, kidney, bone and adrenal gland. Adrenal tuberculosis was seen in 52 of the 871 patients (6%) with active tuberculosis at autopsy and in 3 patients at adrenalectomy. The adrenal gland was the only organ involved by active tuberculosis in 14 of these 55 patients (25%; 35 men, 20 women). Tuberculosis was evident on macroscopic examination of the adrenal glands in 46% of the patients. On histological examination, caseous necrosis and granulomatous inflammation with Langhan's giant cells were seen in 71% and 40% of patients, respectively. Seven patients presented with signs and symptoms of Addison's disease due to bilateral adrenal involvement. Langhan's giant cells were frequently seen in histological sections and bilateral enlargement of the adrenal glands was often noted. Fine needle aspiration cytology was not useful for diagnosing adrenal tuberculosis.

CONCLUSION Unexpected and extra‐pulmonary tuberculosis such as adrenal tuberculosis has been a common problem. A high index of suspicion, correct diagnosis and proper treatment are essential for the management of tuberculosis.
Elderly subjects show severe impairment of dehydroepiandrosterone sulphate and reduced sensitivity of cortisol and aldosterone response to the stimulatory effect of ACTH1−24
Authors: Giordano Roberta , Di Vito Lidia , Lanfranco Fabio , Broglio Fabio , Benso Andrea , Gianotti Laura , Grottoli Silvia , Ghigo Ezio , Arvat Emanuela
Published: March 2003

OBJECTIVE Hyperactivity of the hypothalamic‐pituitary‐adrenal (HPA) axis in ageing has been reported both in humans and in animals and may be involved in age‐related changes in body composition, structure functions and metabolism, as well as in brain ageing. Despite the supposed HPA hyperactivity and its refractoriness to negative glucocorticoid feedback, low levels of dehydroepiandrosterone (DHEA) and its sulphate have been clearly demonstrated in human ageing and may suggest another cause of age‐related changes in structure function and metabolism. Thus, our aim was to verify the adrenal responsiveness to various ACTH doses in normal elderly subjects.

DESIGN We studied cortisol (F), aldosterone (A) and DHEA responses to the sequential administration of very low, low and supramaximal ACTH1−24 doses (0·06 µg or 0·5 µg followed by 250 µg ACTH1−24 i.v. at 0 and +60 minutes) in healthy elderly subjects (ES) [six females and two males, aged 63–75 years, body mass index (BMI) 22–26 kg/m2]. The results in ES were compared with those recorded in healthy young subjects (YS) (six females and six males, aged 22–34 years, BMI 20–25 kg/m2).

RESULTS Basal DHEA levels in ES were lower (P < 0·05) than in YS, while F and A levels were similar in both groups. DHEA, F and A responses to ACTH were dose‐dependent in both groups. In ES, however, DHEA levels showed no response to the 0·06 µg dose, a modest increase after 0·5 µg and a clearer rise after 250 µg ACTH; at any dose, the DHEA response in ES was clearly lower than in YS (P < 0·04). The F responses to 0·5 µg and 250 µg ACTH in ES were similar to those in YS; whereas, in ES, 0·06 µg ACTH elicited a non significant F increase which was significantly lower than in YS (P < 0·05). Similarly, the A responses to the highest ACTH doses were similar in both groups but, in ES, 0·06 µg ACTH elicited no increase in A secretion, which was clearly lower than in YS (P < 0·03).

CONCLUSIONS Normal elderly subjects show severe reduction of DHEA response to a wide range of ACTH doses, in agreement with peculiar impairment of the activity of the adrenal reticularis zone in ageing. In contrast to young adults, elderly subjects also show no cortisol and aldosterone response to a very low ACTH dose. This evidence indicates a reduced sensitivity to ACTH in the fasciculata and glomerulosa zones of the adrenal gland in ageing.
Marked improvement in cardiovascular function after successful transsphenoidal surgery in acromegalic patients
Authors: Minniti Giuseppe , Moroni Carlo , Jaffrain‐Rea Marie‐Lise , Esposito Vincenzo , Santoro Antonio , Affricano Cesare , Cantore Giampaolo , Tamburrano Guido , Cassone Rosario
Published: March 2003

OBJECTIVE Transsphenoidal surgery results in biochemical remission of acromegaly in 45–80% of patients; however, few studies have addressed the impact of transsphenoidal surgery on cardiovascular function in acromegalic patients. The aim of this prospective study was to investigate the effects of postoperative GH/IGF‐I normalization on echocardiographic parameters and blood pressure (BP) in a series of patients with active acromegaly.

DESIGN An open prospective study.

PATIENTS Thirty newly diagnosed acromegalic patients undergoing transsphenoidal surgery.

MEASUREMENTS Doppler echocardiography and 24‐h ambulatory blood pressure monitoring were performed before and 6 months after transsphenoidal surgery.

RESULTS Fifteen patients were considered to be well controlled postoperatively (group A), as defined by normal age‐corrected IGF‐I levels and glucose‐suppressed GH levels less than 2 mU/l, the remaining 15 patients being considered as poorly controlled (group B). In group A, a postoperative decrease of left ventricular mass index was observed (104·4 ± 6·6 vs. 127·1 ± 7·7 g/m2; P < 0·001), associated with an improvement of some indices of diastolic function, such as an increase of the early/late transmitral peak flow velocity (P < 0·05) and a decrease of isovolumic relaxation time (P < 0·01). No significant change was observed in group B. A significant decrease of 24‐h systolic BP was also observed in group A (P < 0·05) and five of six patients normalized their BP circadian rythm. In contrast, a nonsignificant increase in BP values, with a persistent blunted BP profile where present, was observed in group B.

CONCLUSIONS We conclude that successful transsphenoidal surgery is able to induce a significant improvement in some cardiac parameters and a slight reduction in systolic blood pressure in acromegalic patients.
Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants
Authors: Kelleher S. , Conway A. J. , Handelsman D. J.
Published: March 2003

BACKGROUND Implantation of testosterone pellets under the lateral abdominal wall skin is an old but popular and effective form of androgen replacement therapy. Extrusion of one or more pellets remains the most frequent adverse event.

OBJECTIVE To determine whether an alternative implantation site (hip) and/or track geometry (two vs. four tracks) would reduce extrusion rates compared with the standard of a four‐track abdominal site. Additionally, the study aimed to evaluate the effects of site and track geometry on other adverse effects (bruising, infection) and the pharmacology of testosterone release from the implants.

DESIGN A prospective, parallel‐group unmasked study design in a single centre. The primary objective was to evaluate sites, with evaluation of track geometry a subordinate objective made necessary by anatomical differences. Accordingly, androgen deficient men requiring testosterone implantation with the standard dose (four 200 mg pellets) were randomized into one of three groups (ratio 1 : 1 : 2): a four‐track abdomen site (standard), a two‐track abdomen site or a two‐track hip site. The pharmacological substudy was to evaluate the impact of site and track geometry on testosterone implant pharmacology by monthly hormone assays following implantation.

PATIENTS Two hunded and forty‐six implantation procedures involving 96 androgen deficient men.

MEASUREMENTS The primary end‐point, extrusion rate per procedure, and secondary end‐points (bruising or infection post procedure) were evaluated prospectively by self‐report from the participants, and verified when they returned next for implantation. The pharmacology substudy involved monthly blood sampling for hormone (total and free testosterone, LH, FSH) measurements.

RESULTS The extrusion rate was significantly higher [odds ratio (OR) = 2·6, 95% confidence interval (CI) 1·1–7·1] for the hip site (15/125, 12%) compared with the abdominal site (6/121, 5%). Track geometry made no significant difference (OR = 1·05, 95% CI 0·2–5·4) to the extrusion rate. No secondary end‐points (bruising, infection) were significantly different according to either site or track geometry. One operator who performed the implant procedures had significantly less primary and secondary adverse events than the other operators (P = 0·006). Neither implantation site, nor track geometry influenced pharmacokinetics [peak plasma total and free testosterone concentrations and net hormone release (area‐under‐curve, AUC)] or pharmacodynamics [nadir plasma LH and FSH and net suppression (AUC) in men with hypergonadotrophic hypogonadism].

CONCLUSIONS We conclude that the hip site has a higher extrusion rate than the standard abdominal wall site but that track geometry does not increase the risk of extrusion. Neither implantation site, nor track geometry influenced either other adverse effects or the pharmacokinetics or pharmacodynamics of testosterone pellet implants.
Chronic hypocalcaemia due to selective skeletal resistance to parathyroid hormone
Authors: Tucci Joseph R.
Published: March 2003

A 71‐year‐old man was referred for evaluation of asymptomatic hypocalcaemia dating back at least 20 years. There were no somatic abnormalities and Chvostek and Trousseau signs were negative. Serum total calcium varied from 1·88 to 2·03 mmol/l, albumin 37–44 g/l, phosphate 0·54–1·12 mmol/l and ionized calcium 1–1·13 mmol/l. Serum intact PTH levels were 69 and 55 ng/l (10–65), 25‐OHD was 40 nmol/l (2·25–107·5) and 1,25‐(OH)2D was 54·6 nmol/l (39–156). Serum and urine magnesium and creatinine clearance were normal. Twenty‐four‐hour urine calcium was 2.15 mmol and calcium/creatinine ratio 0·07. TM phosphate (maximal rate of tubular reabsorption of phosphate in mmol/l glomerular filtrate (GF)) was 0·84 mmol/l GF (0·80–1·34). Bone formation and resorption markers were normal. Bone mineral densities measured by dual‐energy X‐ray absorptiometry (DEXA) were within normal limits at the hip, forearm and lumbar spine. Infusion of 200 units of synthetic 1–34 PTH was associated with a rise in urinary cyclic AMP from 43 mmol/l GF to 344 mmol/l GF and TM phosphate fell from 0·93 to 0·76 mmol/l GF; 1–34 PTH infusions of 300 units twice daily for 5 days were associated with an increase in serum 1,25‐(OH)2D from 80·6 to 114·4 pmol/l but no increase in serum calcium. This is a most unusual case of chronic hypocalcaemia similar to that reported by Frame et al. resulting from isolated skeletal resistance to PTH that is not related to renal insufficiency, osteomalacia or a magnesium‐deficient state. These two cases appear to represent a new variant of pseudohypoparathyroidism ?type III.
Effect of digoxin on the somatotroph responsiveness to growth hormone‐releasing hormone (GHRH) alone or combined with arginine in normal young volunteers
Authors: Broglio Fabio , Benso Andrea , Gottero Cristina , Di Vito Lidia , Granata Riccarda , Arvat Emanuela , Bobbio Marco , Trevi Giampaolo , Ghigo Ezio
Published: March 2003

BACKGROUND The activity of the GH/IGF‐I axis, known to play a major role in myocardial structure and function, has been reported to be altered in patients with chronic heart failure.

AIM AND DESIGN OF THE STUDY In order to evaluate the possibility that clinically used cardioactive drugs may exert neuroendocrine influences on somatotroph secretion, we studied the effects of pretreatment with enalapril (20 mg/day orally for 3 days), furosemide (20 mg i.v. as a bolus at − 5 minutes) or digoxin (0·25 mg orally 4×/day for 3 days) on the GH response to growth hormone‐releasing hormone (GHRH) (1·0 µg/kg i.v. as a bolus at 0 minutes) in 12 healthy male adults (age [mean ± SEM] 30·2 ± 1·4 years; BMI 22·7 ± 0·7 kg/m2). In a subgroup of 8 subjects the same study was performed testing the GH response to GHRH + arginine (ARG; 0·5 g/kg i.v. from 0 to + 30 minutes).

RESULTS The GH response to GHRH (1304·1 ± 248·5 µg/l/h) was not modified by enalapril (1368·7 ± 171·2 µg/l/h) or by furosemide (1269·3 ± 185·2 µg/l/h) but was significantly blunted by digoxin (613·6 ± 73·2 µg/l/h, P < 0·05). On the other hand digoxin, enalapril and furosemide did not modify the GH response to GHRH + ARG.

CONCLUSIONS Digoxin, but not enalapril or furosemide, inhibits the GH response to GHRH in normal subjects. The blunting effect of digoxin on the GHRH‐induced GH response is counteracted by arginine. These findings show that digoxin possesses an inhibitory effect on somatotroph secretion that may be mediated at the hypothalamic level.
Low individualized growth hormone (GH) dose increased renal and cardiac growth in young adults with childhood onset GH deficiency
Authors: Link Katarina , Bülow Birgitta , Westman Kerstin , Salmonsson Eva Cecilia , Eskilsson Jan , Erfurth Eva Marie
Published: March 2003

OBJECTIVE In childhood onset GH deficiency (GHD) a reduction in left ventricular mass (LV‐mass) and impairment of systolic function as well an impairment in glomerular filtration rate (GFR) has been shown. The aim of the present study was to assess if a low GH dose resulted in an improvement in morphological and functional parameters of these organs.

DESIGN AND PATIENTS Eleven patients with childhood onset GHD were investigated before and after 10 months of GH treatment at a dose of 1·5 IU/day (range 1–2), corresponding to 0·02 IU/kg/day or 7 μg/kg/day. The GH dose resulted in a serum IGF‐I level in the normal range in all but one patient.

MEASUREMENTS Doppler echocardiography of the heart and ultrasound examination of the kidneys was performed. Glomerular filtration rate (GFR) was estimated with iohexol clearance and urinary proteinuria was measured with 24‐h urinary samples collected for analyses of albumin, alpha‐1‐microglobulin, IgG and albumin/creatinine clearance ratio. Body composition was measured by bioelectric impedance analysis.

RESULTS L V‐mass index increased significantly after GH treatment (P = 0·04), and there was a clear trend for a positive correlation between the increase in serum IGF‐I and the increase in LV‐mass index, although it did not reach significance (r = 0·57, P = 0·07). GH treatment did not increase cardiac fractional shortening. Kidney length increased significantly (P = 0·02) with an average increase of 1 cm (range − 0·5–1·5 cm). No significant changes in median GFR or serum creatinine were recorded. Three patients with subnormal GFR before GH treatment normalized after 10 months of treatment. Urine analysis showed no abnormalities before or after GH treatment. A significant decrease in percentage fat mass was recorded (P = 0·03).

CONCLUSION A low individualized GH dose to adults with childhood onset GHD resulted in an increase in LV‐mass index and kidney length. Re‐establishing GH treatment with a low dose in this patient group can lead to a further somatic maturation of these organs, probably not accomplished previously.
Somatostatin receptor 2 expression in the human endometrium through the menstrual cycle
Authors: Green V. L. , Richmond I. , Maguiness S. , Robinson J. , Helboe L. , Adams I. P. , Drummond N. S. , Atkin S. L.
Published: March 2003

objective Somatostatin mediates its many inhibitory functions through five G‐protein‐coupled receptors (sstr1−5); however, it is not known whether somatostatin or its receptors are present in the endometrium.

design We have used immunohistochemistry on formalin‐fixed paraffin‐embedded sections of normal human endometrium from the menstrual (n = 6), proliferative (n = 15) and secretory (n = 10) stages of the endometrial cycle to determine the pattern of expression of somatostatin receptor (sstr) subtype 2. In addition, we have used quantitative polymerase chain reaction (PCR) to determine the level of expression of the sstr2 mRNA in 17 samples of normal human endometrium.

patients Endometrial tissue had been removed from patients undergoing dilation and curettage (D&C) for menorrhagia and had been determined to be normal histologically.

measurements Immunostaining in the epithelium, endothelium and the stroma of the endometrial sections was characterized and was scored positive or negative. The PCR results were analysed using the software provided to standardize the expression of sstr2 against that of constitutively expressed β‐glucoronidase in the same sample. A final percentage value of the level of sstr2 expression was then determined.

results sstr2 was expressed variably throughout all the stages of the menstrual cycle in the epithelium, the endothelium and the stroma. In particular, the position of sstr2 expression varied in the epithelial cells surrounding the endometrial glands from being basal or diffuse in the proliferative and secretory phase to being lumenal in the menstrual stage. Quantitative PCR showed that 15 of 17 samples expressed sstr2 mRNA and the level of expression between individual samples varied dramatically.

conclusions These data show that sstr2 is present in the endometrium and its location seems to vary through the menstrual cycle.
Prospective 10‐year study of the determinants of bone density and bone loss in normal postmenopausal women, including the effect of hormone replacement therapy
Authors: Wu Fiona , Ames Ruth , Clearwater Judy , Evans Margaret C. , Gamble Greg , Reid Ian R.
Published: March 2003

objective To prospectively assess bone density and the factors determining the rate of bone loss over a 10‐year period of postmenopausal life.

design Prospective, observational study.

methods One hundred and four normal White postmenopausal women, baseline mean age 59 years (range 47–71 years) completed the study (mean duration of follow‐up 10·2 years, range 9·4–10·6 years). None had diseases or were taking medications affecting bone metabolism at entry to the study. Information was collected on medical, fracture and smoking history, alcohol use, dietary calcium intake and physical activity. Body composition and bone density were measured by dual‐energy X‐ray absorptiometry at baseline and at 10 years. Biochemical, haematological and hormonal analyses were performed.

results Twenty‐four percent of the women started hormone replacement therapy (HRT) during the study period; most of these remained on therapy at follow‐up. The mean duration of therapy was 6·6 years (range 2·8–10·4 years). The use of HRT was associated with significant gains in bone density (total body + 3·0%, trochanter + 4·2%, Ward's triangle + 4·4%, spine + 10·5%) and a significant reduction in vertebral fracture risk [standardized risk ratio compared with non‐HRT users 0·42 (confidence interval 0·18–0·83)]. HRT use was not associated with greater weight gain than that occurring in other members of the cohort. The baseline and follow‐up bone densities in the non‐HRT users were highly correlated (0·82 ≤ r ≤ 0·91, P ≤ 0·0001) and baseline bone density accounted for the majority of the variance in the 10‐year results. Multivariate analyses showed that the independent correlates of rate of change of bone density were weight and fat mass (both baseline values and changes during follow‐up), time after menopause, sex hormone concentrations, urinary calcium loss, PTH levels and haemoglobin concentration (which may reflect nutrition and health).

conclusions Bone density is highly predictable over an extended period of time in normal postmenopausal women. Maintenance of body weight and good health reduce bone loss. HRT is effective for treating osteoporosis, with improvement in bone density and reduction in vertebral fractures. Good compliance with HRT long‐term is achievable. These findings are relevant to deciding the frequency of bone density measurement, and in advising women regarding prevention and treatment of postmenopausal bone loss.
Endocrine responses to ghrelin in adult patients with isolated childhood‐onset growth hormone deficiency
Authors: Aimaretti Gianluca , Baffoni Claudia , Broglio Fabio , Janssen Joop A. M. , Corneli Ginevra , Deghenghi Romano , Van Der Lely Aart Jan , Ghigo Ezio , Arvat Emanuela
Published: March 2003

objective Ghrelin, a 28 amino acid acylated peptide, is a natural ligand of the GH secretagogues (GHS) receptor (GHS‐R), which is specific for synthetic GHS. Similar to synthetic GHS, ghrelin strongly stimulates GH secretion but also displays significant stimulatory effects on lactotroph and corticotroph secretion. It has been hypothesized that isolated GH deficiency (GHD) could reflect hypothalamic impairment that would theoretically involve defect in ghrelin activity.

patients In the present study, we verified the effects of ghrelin (1 µg/kg i.v.) on GH, PRL, ACTH and cortisol levels in adult patients with isolated severe GHD [five males and one female, age (mean ± SEM) 24·7 ± 2·6 years, BMI 25·7 ± 2·7 kg/m2]. In all patients, the GH response to insulin‐induced hypoglycaemia (ITT, 0·1 IU regular insulin i.v.) and GH releasing hormone (GHRH) (1 µg/kg i.v.) + arginine (ARG, 0·5 g/kg i.v.) was also studied. The hormonal responses in GHD were compared with those in age‐matched normal subjects (NS, seven males, age 28·6 ± 2·9 years, BMI 22·1 ± 0·8 kg/m2).

results IGF‐I levels in GHD were markedly lower than in NS (69·8 ± 11·3 vs. 167·9 ± 19·2 µg/l, P < 0·003). Ghrelin administration induced significant increase in GH, PRL, ACTH and cortisol levels in all GHD. In GHD, the GH response to ghrelin was higher (P < 0·05) than that to GHRH + ARG, which, in turn, was higher (P < 0·05) than that to ITT (9·2 ± 4·1 vs. 5·3 ± 1·7 vs. 1·4 ± 0·4 µg/l). These GH (1 µg/l = 2 mU/l) responses in GHD were markedly lower (P < 0·0001) than those in NS (ghrelin vs. GHRH + ARG vs. ITT 92·1 ± 16·7 vs. 65·3 ± 8·9 vs. 17·7 ± 3·5 µg/l). In GHD, the highest individual peak GH response to ghrelin was markedly lower than the lowest peak GH response in NS (28·5 vs. 42·9 µg/l). GHD and NS showed overlapping PRL (1 µg/l = 32 mU/l) (10·0 ± 1·4 vs. 14·9 ± 2·2 µg/l), ACTH (22·3 ± 5·3 vs. 18·7 ± 4·6 pmol/l) and cortisol responses (598·1 ± 52·4 vs. 486·9 ± 38·9 nmol/l).

conclusions This study shows that ghrelin is one of the most powerful provocative stimuli of GH secretion, even in those patients with isolated severe GHD. In this condition, however, the somatotroph response is markedly reduced while the lactotroph and corticotroph responsiveness to ghrelin is fully preserved, indicating that this endocrine activity is fully independent of mechanisms underlying the GH‐releasing effect. These results do not support the hypothesis that ghrelin deficiency is a major cause of isolated GH deficiency but suggest that ghrelin might represent a reliable provocative test to evaluate the maximal GH secretory capacity provided that appropriate cut‐off limits are assumed.
Chromogranin ‘A’ in normal subjects, essential hypertensives and adrenalectomized patients
Authors: Giampaolo Bernini , Angelica Moretti , Antonio Salvetti
Published: March 2003

objective Chromogranin A (CgA) is an acidic glycoprotein co‐stored in vesicles and co‐released with catecholamines. Although currently used as a humoral marker of endocrine tumours, several aspects of CgA secretion still need to be clarified in humans.

patients Fifty‐four controls, 83 essential hypertensive and six adrenalectomized patients were studied.

design In the controls and hypertensive patients, CgA and catecholamines were measured before (supine position) and after changes in posture (2′ upright position), insulin‐induced hypoglycaemia (0·15 IU/kg i.v.) and glucagon injection (1 mg i.v.). In addition, blood samples were taken in the morning (0800 h) and in the afternoon (1800 h), and every 5 h for 24 h. In the adrenalectomized patients, blood samples were obtained in the morning and in the afternoon.

measurements CgA was measured by an immunoradiometric assay, and noradrenaline and adrenaline by high‐performance liquid chromatography.

results In controls, posture slightly increased plasma catecholamines without affecting CgA levels. Hypoglycaemia evoked a rise in noradrenaline (P < 0·04), adrenaline (P < 0·01) and CgA (79·6 ± 11·8 vs. 46·1 ± 10·1 µg/l, P < 0·03). Glucagon injection increased plasma adrenaline (P < 0·01) but not noradrenaline or CgA levels. At variance with blood pressure and catecholamines, CgA increased significantly in the afternoon (51·1 ± 4·0 vs. 45·0 ± 3·9 µg/l, P < 0·05); it also had a circadian rhythm, with peak values during the night (at 2300 h, 65·4 ± 9·0 µg/l) and a nadir in the morning (at 0800 h, 43·1 ± 6·6 µg/l). In hypertensives, basal and stimulated CgA levels as well as diurnal/circadian variations of this peptide were similar to those in normal subjects. In adrenalectomized patients plasma CgA in the morning (34·3 ± 6·5 µg/l) was lower (P < 0·03) than in all controls and hypertensives studied, but also showed an afternoon increment (46·4 ± 6·6 µg/l, P < 0·003). No correlation was found between CgA and catecholamines or blood pressure in all subjects or in the subgroups.

conclusions In normal humans, chromogranin A and catecholamines are not always co‐secreted, and co‐secretion occurs only for marked exocytotic adrenergic stimuli, such as hypoglycaemic stress. In addition, chromogranin A has a circadian rhythm unrelated to plasma catecholamines. Basal plasma concentrations and the secretory pattern of chromogranin A in hypertensives do not differ from the findings in controls. Finally, the adrenal glands contribute partially to circulating chromogranin A and are not involved in the circadian rhythm of this peptide in humans.
West syndrome and mitochondrial diabetes: relationship or coincidence?
Authors: Bouhanick B. , Reynier P. , Salle A. , Ilhouz F. , Coutant R. , Pouplard F.
Published: March 2003

West syndrome occurs in infancy and in early childhood. It is characterized by intractable seizures occurring almost daily, severe psychomotor retardation, poor prognosis and EEG abnormalities, known as hypsarrhythmia. We report here the case of a 28‐year‐old patient, who was diagnosed with West syndrome when he was 8 months old and with diabetes mellitus when he was 25 years old. Sequencing analyses and restriction analyses were suggestive of mitochondrial diabetes. Four years after the diagnosis of diabetes, this patient's diabetes is still controlled by diet and biguanides.
A case of primary mucoepidermoid carcinoma of the thyroid: molecular evidence of its origin
Authors: Minagawa Akinobu , Iitaka Makoto , Suzuki Miho , Yasuda Shigemitsu , Kameyama Kaori , Shimada Shio , Kitahama Shinji , Wada Seiki , Katayama Shigehiro
Published: March 2003

Primary mucoepidermoid carcinoma (MEC) of the thyroid is very rare, and its origin has not been fully determined. We report a case of MEC, the origin of which was demonstrated by thyroid specific genes expressed in a metastatic lymph node. A 52‐year‐old male presented with chest pain, weight loss and diffuse goitre. Ultrasonography showed the thyroid to be diffusely enlarged with numerous small calcifications. The tumour was found to be infiltrating the thyroid, lung, lymph nodes and first thoratic vertebra. A variant type of papillary thyroid carcinoma was suspected by fine needle aspiration cytology of the thyroid. An open biopsy specimen from an axillary lymph node revealed the tumour to be composed of three distinct cell types: mucin‐producing cells, intermediate cells and a small amount of epidermoid cells with scattered psammoma bodies. Immunohistochemical studies showed the tumour cells to be negative for thyroglobulin and calcitonin, but positive for CEA. To examine the primary origin of the tumour, the expression of thyroid specific genes in the lymph node specimen was examined by RT‐PCR. TTF‐1, TTF‐2, Pax‐8, Na‐I symporter and thyroid peroxidase mRNA were detected. The presence of these thyroid‐specific mRNAs indicates that this MEC originated from thyroid follicular epithelium. This is the first molecular evidence of dedifferentiation from thyroid follicular cells to MEC.