bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing's syndrome due to ACTH‐independent bilateral macronodular adrenocortical hyperplasia
Authors: Daidoh  , Morita  , Hanafusa  , Mune  , Murase  , Sato  , Shibata  , Suwa  , Ishizuka  , Yasuda
Published: March 2003

We examined the possibility that AVP and V1a receptors were involved in regulating cortisol production in a 49 year old man with ACTH‐independent bilateral macronodular adrenocortical hyperplasia (AIMAH), and investigated the effects of a V1a receptor antagonist. An iv injection of a small dose (0.1 or 0.3 U) of AVP, insulin‐induced hypoglycaemia, upright posture tests, and oral administration of a V1a receptor antagonist (OPC‐21268; 300 mg), and its repeated administration at a dose of 600 mg/day for 8 days were performed. An in vitro study of dispersed cells obtained from resected AIMAH tissue was also conducted. Plasma ACTH, AVP and cortisol levels and 24‐h urinary free cortisol excretion were measured in the in vivo studies and cortisol concentrations in incubation media in the in vitro study. Injection of small doses of AVP stimulated cortisol secretion without any elevation of plasma ACTH. Insulin‐induced hypoglycaemia caused a rise in plasma AVP followed by an increase in plasma cortisol. Although plasma cortisol levels were not affected by single or repeated administrations of OPC‐21268, 24‐h urinary free cortisol excretion was significantly decreased by the repeated treatment. In the in vitro study, more cortisol was stimulated by AVP from adrenal cells of the AIMAH tissue than from those of a normal adrenal gland, and this secretion was completely suppressed by OPC‐21268. These results suggested that hypersensitivity to AVP may have contributed to overproduction of cortisol in this case of ACTH‐independent bilateral macronodular adrenocortical hyperplasia, and may have contributed to its pathogenesis.
Sexual dimorphism in 11 β hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects
Authors: Weaver Jolanta U , Taylor Norman F , Monson John P , Wood Peter J , Kelly William F
Published: March 2003

OBJECTIVE

Sexual dimorphism of 11 β hydroxysteroid dehydrogenase activity (11 β HSD) as measured by the urinary 11‐OH/11‐oxo cortisol metabolite ratio has been documented in healthy subjects. Since body composition, fat distribution and insulin sensitivity vary between the sexes we have investigated whether these factors may account for the observed difference. Studies were performed in ACTH deficient hypopituitary subjects to eliminate the effect of feedback modulation of cortisol secretion.

DESIGN AND PATIENTS

44 hypopituitary patients, (m:f, 32:12), median age 51 years, median weight 86 kg, on hydrocortisone and other replacement therapy as appropriate were studied.

MEASUREMENT

Urine 11‐OH/11‐ oxo cortisol metabolites and serum and urine cortisone (E) and cortisol (F) were measured in relation to total cortisol metabolites and cortisol binding globulin; fat distribution was assessed by Dual Energy X‐ray absorptiometry (DXA), and insulin sensitivity by homeostatic model of assessment.

RESULTS

Cortisol bioavailability (total urine cortisol metabolites, urine free cortisol and cortisol binding globulin) was similar in both sexes. The 11‐OH/11‐oxo ratio was lower in females than males (median; 0.99 vs 1.3, P < 0.03) while thyroid status was similar. Females had higher percentage fat (median 47.7 vs 34.9, P < 0.01); total fat (median 39.5 vs 34.9 kg, P < 0.01), android fat (median 9.1 vs 6.6 kg, P < 0.01); gynoid fat (median; 9.9 vs 6.8 kg, P < 0.05) and lower insulin sensitivity (median 15.3 vs 30.6, P < 0.01). In all subjects, the 11‐OH/11‐ oxo ratio was inversely related to body weight (P < 0.01), % fat (P < 0.05), total fat (P < 0.01), android fat (P < 0.01), gynoid fat, (P < 0.01) and directly correlated to insulin sensitivity, P < 0.01. Stepwise regression analysis showed gynoid fat to be the most important factor determining the 11‐OH/11‐oxo ratio. In 24 subjects (f : m, 8 :16) on exogenous sex steroid therapy insulin sensitivity was similar but the sexual dimorphism of the 11‐OH/11‐oxo ratio remained unchanged (median; 1.0 vs 1.7, P < 0.05). The urine and serum F and E and their ratio (F/E) were similar in these groups.

CONCLUSION

These data confirm the presence of sexual dimorphism in 11 β‐hydroxysteroid dehydrogenase activity in hypopituitary patients as described in normal individuals. This is the first in vivo evidence that this dimorphism is related to body composition. Our findings suggest that sexual dimorphism may be determined by the activity of type 1 and not type 2 11 β‐hydroxysteroid dehydrogenase.
Neurohypophysial hormone and melatonin secretion over the natural and suppressed menstrual cycle in premenopausal women
Authors: Kostoglou‐Athanassiou Ifigenia , Athanassiou Panagiotis , Treacher David F , Wheeler Michael J , Forsling Mary L
Published: March 2003

OBJECTIVE

Vasopressin, oxytocin and melatonin have been reported to be influenced by ovarian steroids. The neurohypophysial hormones have also been shown to display a diurnal pattern of secretion in men. We therefore studied the diurnal pattern of neurohypophysial hormone and melatonin secretion in premenopausal women and in women on oral contraceptives.

DESIGN

Healthy normally cycling premenopausal women were studied over 24 hours during the midfollicular and midluteal phases of the menstrual cycle. Healthy premenopausal women on oral contraceptives were studied over 24 hours at similar times.

SUBJECTS

Eight healthy normally cycling women and 7 healthy premenopausal women on oral contraceptives.

MEASUREMENTS

Plasma vasopressin, oxytocin and melatonin were measured by radioimmunoassay.

RESULTS

Vasopressin concentrations and its nocturnal peak were highest in the follicular phase of the natural menstrual cycle and attenuated in the women on oral contraceptives. Oxytocin concentrations did not vary between the two phases of the menstrual cycle, but increased on oestrogen administration. Overall melatonin secretion was augmented in the women on oral contraceptives.

CONCLUSIONS

Vasopressin release and its nocturnal peak were greatest in the follicular phase of the menstrual cycle, while melatonin secretion was augmented in the women on oral contraception.
The impact of obesity on cardiovascular risk factors in Turner's syndrome
Authors: Elsheikh Mohgah , Conway Gerard S.
Published: March 2003

OBJECTIVE

To evaluate risk factors for coronary artery disease in women with Turner's syndrome which may contribute to the increased incidence of premature cardiovascular death noted in this disorder.

DESIGN

Comparison of clinical and biochemical parameters in women with Turner's syndrome with those in women with normal karyotype.

PATIENTS

Ninety‐one women with Turner's syndrome attending a dedicated adult Turner's syndrome clinic and 22 control subjects were studied.

MEASUREMENTS

Recumbent blood pressure, body mass index (BMI), fasting total cholesterol, triglycerides and high density lipoproteins (HDL) were measured in both study groups.

RESULTS

Women with Turner's syndrome were more obese compared with women with a normal karyotype. They were more likely to be hypertensive and the obese patients had higher serum triglyceride concentrations. Hypertension was independent of obesity and may be under‐recognized because of failure to compare with age‐matched normal ranges. Lipoprotein changes were accounted for by the obesity.

CONCLUSIONS

Women with Turner's syndrome may be at increased risk of developing coronary artery disease as a result of the higher frequency of hypertension and obesity. Routine screening of this population for risk factors for ischaemic heart disease is recommended.
Inhibin B levels in azoospermic subjects with cytologically characterized testicular pathology
Authors: Foresta Carlo , Bettella Andrea , Petraglia Felice , Pistorello Matteo , Luisi Stefano , Rossato Marco
Published: March 2003

BACKGROUND AND OBJECTIVE

Inhibin B, a heterodimeric glycoprotein of gonadal origin, is the most important circulating form of inhibin in human males and an inverse relationship between inhibin B and FSH plasma levels was been recently observed. Azoospermia represents the end‐point of different kinds of testicular damage, ranging from a normal spermatogenic pattern (obstructive forms) to the complete absence of germ cells (Sertoli Cell Only Syndrome, SCOS). Furthermore, azoospermia may be related to maturational disturbances at different levels (spermatogonial, spermatocytic, spermatidic). To better define the relationship between testicular damage and inhibin levels and to evaluate the diagnostic value of this hormone in the management of subjects with azoospermia, we performed specific inhibin B assays in a group of azoospermic subjects affected by different kinds of testicular pathology.

PATIENTS

Eighty‐nine azoospermic men were studied by testicular ultrasound examination, fine needle aspiration of the testes and hormonal parameters (FSH, LH and testosterone, inhibin B). Thirty normozoospermic subjects were considered as controls for seminal and hormonal parameters.

DESIGN AND RESULTS

On the basis of cytological analysis five different testicular appearences were identified in azoospermic patients: (i) Sertoli cell only syndrome (SCOS); (ii) Severe hypospermatogenesis; (iii) Spermatogonial and/or spermatocytic arrest; (iv) Spermatidic arrest; (v) Normal germ line (obstructive forms). No difference in LH and testosterone levels was found among the different groups. A significant negative correlation was present between inhibin B and FSH both in azoospermic men (r = − 0.503, P < 0.0001) and normozoospermic controls (r =−0.361, P < 0.05). Groups characterized by obstructive azoospermia and spermatidic arrest showed inhibin B concentrations similar to normozoospermic subjects (130.7 ± 73.5, 160.3 ± 35.1 and 148.5 ± 46.8 ng/l, respectively), while groups characterized by SCOS, severe hypospermatogenesis and spermatogonial and/or spermatocytic arrest showed mean inhibin B concentrations significantly lower than controls (56.5 ± 56.0, 57.9 ± 31.2; 48.9 ± 16.7 ng/l, respectively). In the group of SCOS, 8 out of 42 subjects (19.0%) showed inhibin B concentrations within the normal range despite high FSH levels.

CONCLUSIONS

This study demonstrated that, in humans, spermatids play an important role in the mechanism regulating inhibin B secretion by Sertoli cells. The significance of this hormone as a diagnostic parameter in azoospermic patients does not seem to be specific because it does not permit discrimination between obstructive forms or spermatidic arrest. Furthermore, despite an evident clinical, cytological and hormonal pattern for SCOS, inhibin B levels are normal in some of these patients. The significance of this latter result remains to be elucidated.
Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey
Authors: Bennedbæk Finn Noe , Perrild Hans , Hegedüs Laszlo
Published: March 2003

BACKGROUND AND OBJECTIVE

The optimum diagnostic and therapeutic strategy for the euthyroid patient with a solitary thyroid nodule is still a matter of debate. The aim was to assess the attitudes towards management of such patients in clinical centres throughout Europe by means of a questionnaire.

DESIGN

The questionnaire was circulated to all clinical members of the European Thyroid Association (ETA). A case report was followed by diagnostic investigations and choice of therapy in the index case (a 42‐year old woman with a solitary 2 × 3 cm thyroid nodule and no clinical suspicion of malignancy). Eleven variations of the basic case report were proposed in order to evaluate how each alteration would affect management.

MATERIAL

151 members replied to the letter and 110 individuals from 20 countries completed the questionnaire (corresponding to approximately two‐thirds of the clinical members of the ETA). They represented clinicians who had diagnosed and treated more than 50 (76%) or less than 50 (24%) patients with nodular thyroid disease within the previous 6 months.

RESULTS

Based on the index case, basal serum TSH was the routine choice of 99% and serum T4 and/or free T4 were included by 70% of the respondents. Almost 50% included determination of serum thyroid autoantibodies (TPOab: 47%, Tgab:26%) and 43% measured serum calcitonin. Thyroid scintigraphy was used by 66% (99mTc: 86%, 123I: 10%, 131I: 4%), ultrasonography (US) by 80% (size: 75%, grey scale: 57%, Doppler: 33%). Scintigraphy in addition to US was used by 58%. Fine‐needle aspiration biopsy (FNAB) was routinely used by 99% of the respondents, and performed under US‐guidance by 42%. Based on the individually chosen diagnostic tests indicating a benign solitary thyroid nodule, a non‐surgical strategy was advocated by 77%. Despite controversies on L‐T4 treatment this treatment was supported by more than 40% of the clinicians. Surgery was advocated by 23% and the preferred technique was hemithyroidectomy (70%). Clinical factors raising suspicion of thyroid malignancy (e.g. family history of thyroid cancer, history of external radiation, rapid nodule growth and a large nodule of 5 cm) lead the majority (70–91%; P < 0.000001) to disregard FNAB results and to choose a surgical strategy.

CONCLUSIONS

The favoured diagnostic strategy in the workup of patients with a solitary thyroid nodule include determinations of serum TSH combined with serum T4 and/or free T4 followed by FNAB and US together with scintigraphy. A nonsurgical strategy was favoured by the majority supporting the use of L‐T4 as the first choice. In case of clinical factors raising the likelihood of malignancy, the majority recommended diagnostic thyroidectomy despite FNAB suggesting a benign condition.
Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH)
Authors: Lee Edwin , Chen Peijun , Rao Harsha , Lee Jenifer , Burmeister Lynn A.
Published: March 2003

OBJECTIVE

The interpretation of thyroid function tests in the setting of severe illness is often complicated by concomitant drug administration which may independently produce changes in thyroid hormone concentrations or even secondary hypothyroidism. Although the effects of dopamine on TSH are well established, the effects of dobutamine, another drug commonly used in the setting of severe illness, on TSH are unknown. The aim of the study was to establish the effect(s) of acute high dose dobutamine on serum TSH concentration.

DESIGN AND PATIENTS

Thirty subjects undergoing dobutamine stress echocardiogram were compared to twenty controls. Serum TSH was determined between the hours of 0800 and 1000 h at baseline, at maximum dobutamine infusion (20–50 μg/kg/min and 15 minutes after stopping dobutamine.

MEASUREMENTS

Serum TSH concentration was measured using a third generation chemiluminescent assay.

RESULTS

TSH concentration decreased with time in both dobutamine and control subjects and there was an additional statistically significant effect of dobutamine treatment to decrease TSH. TSH concentration remained within the normal range in all subjects who started with normal TSH concentration and remained above normal in the three dobutamine‐treated subjects with elevated TSH at baseline. The dobutamine‐associated decrease in TSH was still present 15 minutes after discontinuing dobutamine.

CONCLUSIONS

These results indicate that acute high dose dobutamine lowers TSH by an unknown mechanism. Additional study with prolonged dobutamine infusion is needed to establish the steady state level and physiological consequences of dobutamine‐inhibited TSH.
Octreotide‐scintigraphy is a disease‐activity parameter in Graves' ophthalmopathy
Authors: Gerding M. N. , van der Zant F. M. , van Royen E. A. , Koornneef L. , Krenning E. P. , Wiersinga W. M. , Prummel M. F.
Published: March 2003

OBJECTIVE

It is thought that immunosuppressive treatment of Graves' ophthalmopathy should be restricted to patients with active eye disease, but assessing disease activity is difficult. Octreotide scintigraphy has been claimed to differentiate active from inactive disease. Here we study the intraobserver variability and diagnostic accuracy of the quantitative measurement of orbital octreotide uptake.

PATIENTS AND DESIGN

Twenty‐two consecutive patients with moderately severe ophthalmopathy were treated with retrobulbar radiotherapy. Pretreatment octreotide scintigraphic data were related to the response at six months after radiotherapy, using Receiving‐Operator‐Characteristic curves.

MEASUREMENTS

Octreotide uptake was measured at 4 and 24 h after i.v. injection of approximately 3 mCi (= 111 MBq; range 75–150 MBq) 111Indium‐DTPA‐Octreotide with a neuro‐SPECT camera. Counts were measured in fixed regions‐of‐interest in 4 transversal slices of the orbit, the temporal and the occipital area. Measurements were done twice and intraobserver variability was analysed by coefficients of variations (CV). Uptake is expressed as orbital/background ratio. The nature of the temporal uptake was studied by matching an octreoscan with a technetium scan and MRI.

RESULTS

Intra‐observer variability of measuring octreotide uptake was acceptable, and the coefficient of variation slightly better using the orbital/occipital ratio (11%), than the orbital/temporal ratio (16%). From matching studies it appears that the temporal uptake takes place, in part, in the parotid gland. The orbital/occipital ratio was used to predict the outcome of radiotherapy. Mean (± SD) uptake on the 4 h scan was higher in responders (2.2 ± 0.66) than in nonresponders (1.7 ± 0.39; P = 0.04). From the Receiving‐Operator‐Characteristic curve we determined a cut‐off value of 1.85, which yielded a positive predictive value of 92% and a negative predictive value of 70%.The 24 h scan could not predict a response.

CONCLUSION

Quantitative measurement of orbital octreotide uptake is possible. Using the orbital/occipital ratio on the 4 h scan, the octreoscan seems useful in predicting response to subsequent radiotherapy. The 24 h scan seems not to be useful in predicting therapeutic outcome.
Prevalence and significance of thyroid autoantibodies in patients with chronic hepatitis C virus infection: a prospective controlled study
Authors: Huang Miau‐Ju , Tsai Sun‐Lung , Huang Bie‐Yu , Sheen I‐Shyan , Yeh Chau‐Ting , Liaw Yun‐Fan
Published: March 2003

OBJECTIVE

To clarify controversies on the prevalence and clinical significance of thyroid autoimmunity in hepatitis C virus (HCV) infection.

DESIGN

A prospective controlled and follow‐up study.

PATIENTS AND MEASUREMENTS

Serum thyroid microsomal antibody (TMA) and thyroid stimulating hormone were assayed and compared in a consecutive, unselected series of 130 patients with chronic HCV infection, 130 sex/age (± 2 years)‐matched patients with chronic hepatitis B virus (HBV) infection and 260 matched normal controls.

RESULTS

The prevalence of thyroid autoantibodies in male patients with chronic HCV was < 2%. The prevalence of TMA (< 1 : 400) in female patients with chronic HCV infection was significantly higher than that of HBV controls (22.1 vs. 1.6%; P < 0.001), and higher but not significant compared with normal controls (13.5%). However, the trend of increasing prevalence with age in normal controls was not observed in HCV patients. TMA seropositive female HCV patients were not different from seronegative counterparts in age, duration of infection, HLA haplotype, associated autoantibodies and liver histology but had a significantly higher prevalence of genotype 1b/2b mixed infection (P < 0.01) and anti‐GOR (P < 0.05). Of the 23 HCV patients seropositive for thyroid autoantibodies, seven had Hashimoto's thyroiditis, two had Graves' disease and three had received subtotal thyroidectomy. During follow‐up, four of 15 female patients showed a 14–16‐fold increase in TMA titre and one developed hyperthyroidism. Patients with thyroid autoantibodies did not show a propensity to develop thyroid dysfunction during interferon therapy.

CONCLUSIONS

These results suggest a weak association between HCV and thyroid autoimmunity in females. As in the ordinary population with thyroid autoantibodies, they should be evaluated for thyroid status and be followed‐up if thyroid autoimmunity is evident. However, seropositivity of thyroid autoantibodies is not a contraindication to interferon therapy.
Apoptosis in neuroendocrine tumours
Authors: Wang Da‐Gong
Published: March 2003

Acquired resistance to apoptosis in neuroendocrine tumours (NETs) may promote clonal expansion and enhance the likelihood that subsequent mutations lead to growth or persistence of the neoplastic clone. Recent studies have demonstrated that deregulation of programmed cell death may be a critical component in multistep tumourigenesis of NETs and that the frequent expression of the Bcl‐2 oncoprotein in these tumours may contribute to their pathogenesis. The genetic complementation of simultaneously deregulated Bcl‐2 and c‐Myc may be implicated in the multistep tumourigenesis of human NETs.

Furthermore, because the efficacy of cytotoxic chemotherapy relies on its ability to induce programmed cell death, resistance to apoptosis typically correlates with chemoresistance, a phenomenon that is typical in NETs. Consideration of how oncogenes affect rates of cell death, in addition to augmenting growth, has already provided valuable insights into the biology of cancer. Understanding the molecular and cellular features of this process may enable the development and application of more effective and potentially curative treatment strategies in which the induction of programmed cell death is an integral component.
Lipid profile, glucose tolerance and insulin sensitivity after more than four years of growth hormone therapy in non‐growth hormone deficient adolescents
Authors: Bareille Philippe , Azcona Cristina , Matthews David R , Conway Gerard S. , Stanhope Richard
Published: March 2003

OBJECTIVE

To study the effects of long‐term (> 4 years) growth hormone (GH) therapy on insulin sensitivity, glucose tolerance and lipid profile in non‐GH deficient adolescents at completion of their growth.

SUBJECTS

Thirty non‐GH deficient (15 ‘idiopathic’ short stature, 8 intrauterine growth retardation, 7 partial GH deficiency in childhood but normal on retesting) were recruited, median (range) age 16.9 years (15–20.3) prior to ceasing their GH therapy. Their median (range) duration of GH treatment was 7.9 years (4–11). Insulin sensitivity was also recorded in 10 normal controls with a median (range) age of 20.5 years (18.4–22.3).

METHODS

Insulin sensitivity was assessed by a short insulin tolerance test in 18 patients on GH therapy and controls. It was repeated in 14 patients six months after stopping their GH therapy. A 3‐h standard oral glucose tolerance test (OGTT) was performed in 19 patients on GH therapy, and repeated after 6 months off GH in 10 patients. Fasting lipids were also measured.

RESULTS

Insulin sensitivity index was significantly lower in the patients on GH therapy than in the controls, (median (range)) 3.7%/min (1.2–5.3) and 5.3%/min (3.8–6.2), respectively. Six months after termination of GH therapy, insulin sensitivity increased significantly from 3.6%/min (1.2–5) to 4.8%/min (2.8–5.6). Fasting plasma insulin decreased significantly off GH therapy from 10.1 to 3.6 mU/l. The area under the insulin curve during the OGTT was also significantly higher on GH therapy. Apart from one patient with impaired glucose tolerance on GH treatment, plasma glucose concentrations remained within the normal range. No lipid abnormalities were recorded.

CONCLUSIONS

These data suggest that long‐term GH therapy may cause insulin resistance in non GH deficient adolescents, but usually with neither impaired glucose tolerance nor hyperlipidaemia.
Abnormal circadian rhythm and increased non‐pulsatile secretion of thyrotrophin in Sheehan's syndrome
Authors: Maccagnan Paulo , Oliveira Juliana H. A , Castro Vania , Abucham Julio
Published: March 2003

OBJECTIVE

It has previously been shown that patients with postpartum pituitary necrosis (Sheehan's syndrome, SS) have paradoxically increased TSH levels and loss of the nocturnal TSH surge. This study sought to determine the circadian and pulsatile characteristics of TSH secretion underlying those abnormalities.

DESIGN AND PATIENTS

Chronobiological and cluster analyses of 24‐h TSH profiles were performed in nine SS patients (43–61 years, median = 52 years) and nine healthy female controls (33–47 years, median = 42 years).

MEASUREMENTS

Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radioimmunoassay; TSH, GH, PRL and LH were determined by immunometric assays.

RESULTS

All patients and controls showed significant circadian TSH rhythms, but the percentage amplitude was decreased (7.5% vs. 21.3%, P < 0.0001) and the acrophase was markedly displaced in SS patients, occurring between 0315 h and 1515 h in seven/nine patients and in two/nine controls (P = 0.057). Patients showed increased total 24‐h TSH secretion (6054 ± 2293 vs. 2193 ± 340 mU/l/min, mean ± SE, P = 0.04) due to increased non‐pulsatile or tonic 24‐h TSH secretion (5631 ± 2105 vs. 1925 ± 301 mU/l/min, P = 0.026), but no difference was detected in pulsatile secretion (424 ± 191 vs. 268 ± 41, P = 0.82). The contribution of non‐pulsatile to total TSH secretion was also increased in SS patients (93.8% vs. 87.6%, P = 0.002). No significant changes were found in TSH pulse frequency, amplitude, duration or interpeak interval. When cluster parameters were individually analysed in two distinctive 12‐h periods corresponding to acrophase and nadir, patients showed increased non‐pulsatile TSH secretion in both periods, but no differences were found in pulsatile TSH secretion, pulse frequency or amplitude. The increment of TSH secretion during the acrophase in SS patients was exclusively due to increased non‐pulsatile TSH secretion, as opposed to controls who displayed significant increments in both non‐pulsatile and pulsatile TSH secretions.

CONCLUSIONS

Sheehan's syndrome patients have increased total TSH secretion due to increased tonic TSH secretion. A circadian TSH rhythm is still present in these patients, but shows decreased magnitude and markedly displaced acrophase.
Sensitivity and specificity of the fine needle aspiration biopsy of the thyroid: clinical point of view
Authors: Čáp  , Ryška  , Řehořková  , Hovorková  , Kerekes  , Pohnětalová
Published: March 2003

INTRODUCTION

The rates of sensitivity and specificity of fine needle aspiration biopsy (FNAB) for the diagnosis of thyroid malignancy differ considerably among various reported series. These values are influenced by three factors: (a) whether only clearly positive and negative results are considered, or whether the commonly encountered 10–20% of indeterminate/suspicious ones are included; (b) whether adenomas are considered as neoplasms in one group with carcinomas; and (c) whether only histologically proven cases are used in calculations or whether patients with benign clinical follow‐up are included.

AIM

The aim of the study was to evaluate the sensitivity and specificity of FNABs performed at this institution in the last 7 years from the clinical point of view, considering only benign vs. suspicious/malignant FNAB results (indicating surgery), and benign (including adenomas) vs. malignant definitive histology.

STUDY DESIGN

Retrospective study comparing pre‐operative FNAB results with definitive histological examination after operation.

PATIENTS

A total of 2492 FNABs were performed in 2100 patients (1875 women and 225 men); their ages ranged from 9 to 85 years, with a median of 46 years. Clinical diagnosis was multinodular goitre in 1330, single nodule in 591, Hashimoto's thyroiditis in 147 and subacute thyroiditis in 32 cases. In 148 instances, the nodule was cystic. A history of previous treatment for carcinoma of the thyroid was present in 12 patients. Five hundred and thirty‐six patients subsequently underwent thyroid surgery.

STATISTICS

The values of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were calculated.

RESULTS

The sensitivity was 86%, specificity 74%, PPV 34%, NPV 97% and diagnostic accuracy 75%.

CONCLUSIONS

The specificity and positive predictive value are low when fine needle aspiration biopsy results are divided into two categories only (these being indication for surgery or not), and when only suspicious/malignant fine needle aspiration biopsies with subsequent malignant histology are considered to be true positive. Nevertheless, the ability to discriminate 11.7% of patients with a 34% probability of malignancy (suspicious/malignant cytology) from 81.2% of patients (benign cytology) with a probability of only 3% is very helpful.
GIP‐dependent adrenal Cushing's syndrome with incomplete suppression of ACTH
Authors: Croughs Ronald J. M. , Zelissen Pierre M. J. , Van Vroonhoven Theo J. M. V. , Hofland Leo J. , N'diaye Nina , Lacroix André , De Herder Wouter W.
Published: March 2003

ACTH‐independent Cushing's syndrome may be due to the development of ectopic hormone receptors in adrenal tissue. Thus, in food‐dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the case of a 60‐year‐old woman with food‐dependent Cushing's syndrome whose cortisol levels increased after stimulation with CRH. In this patient with Cushing's syndrome the finding of low basal plasma cortisol levels in the late night and early morning as well as a paradoxical rise of plasma cortisol during a 7‐h infusion with dexamethasone (carried out without any restriction in food intake), suggested that cortisol production was stimulated at times of food intake. Hourly measurements of plasma cortisol for 48 h revealed prominent meal‐related peaks. A plasma cortisol response, elicited by oral glucose administration, could be prevented by octreotide. Plasma ACTH was low or undetectable. CRH administration was followed by a ACTH response from 3 to 16 ng/l and a plasma cortisol response from 230 to 680 nmol/l. Octreotide treatment for nearly five months induced a partial clinical and biochemical remission. Total bilateral adrenalectomy was performed. The left adrenal was grossly enlarged (7 × 5.5 × 4 cm) and the right adrenal was slightly enlarged (6 × 4 × 1.8 cm). Microscopy revealed bilateral nodular hyperplasia. Cell suspensions of adrenal tissue from the patient did respond in a dose‐dependent fashion to stimulation with GIP and were very sensitive to stimulation with synthetic ACTH1–24. However, CRH had no significant effect on cortisol production in vitro. Using RT‐PCR amplification and cDNA hybridization, GIP receptor was found to be overexpressed in the left and right adrenal tissues from this patient as compared to adrenal tissues from a normal individual or from non GIP‐dependent adrenal Cushing's syndrome. There was no evidence of presence of adrenal CRH receptors. Thus, in this patient with food‐dependent Cushing's syndrome, the CRH‐induced plasma ACTH and cortisol response is probably mediated by an incomplete suppression of the HPA axis as a result of the intermittent food‐dependent nature of Cushing's syndrome.
Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD65 autoantibodies
Authors: Gambelunghe Giovanni , Forini Francesca , Laureti Stefano , Murdolo Giuseppe , Toraldo Gianluca , Santeusanio Fausto , Brunetti Paolo , Sanjeevi Carani B. , Falorni Alberto
Published: March 2003

OBJECTIVE

Glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) in type 2 diabetic subjects with secondary failure to sulphonylurea treatment identify the so‐called latent autoimmune diabetes of the adult (LADA). The aim of our study was to estimate the risk for endocrine autoimmunity in type 2 diabetic subjects with GAD65Ab.

DESIGN AND PATIENTS

We analysed serum samples from 600 adult subjects with a clinical diagnosis of type 2 diabetes mellitus for the presence and levels of GAD65Ab and antibodies directed against the islet autoantigen IA‐2/ICA512 (IA‐2/ICA512Ab). All the patients had been treated initially with hypoglycaemic agents and/or diet for at least 1 year. GAD65Ab+ subjects were studied for the presence of thyroid peroxidase autoantibodies (TPOAb), 21 hydroxylase autoantibodies (21OHAb) and frequency of HLA class II haplotypes.

RESULTS

GAD65Ab were found in 67/600 (11%) and IA‐2/ICA512Ab in 12/600 (2%) subjects (P < 0.0001). The presence of GAD65Ab, but not that of IA‐2/ICA512Ab, was significantly associated with insulin therapy, low BMI (P < 0.0001) and low basal C‐peptide (P < 0.01). Islet‐cell antibodies (ICA) were detected in 43/67 (64%) GAD65Ab+ and in 10/12 (83%) IA‐2/ICA512Ab + subjects. TPOAb occurred more frequently in GAD65Ab+ (16/67, 24%) than in GAD65Ab‐subjects (9/174, 5%) (P < 0.0001). 21OHAb were detected only in GAD65Ab+ subjects (3/67, 4.5%) (P = 0.03 vs. GAD65Ab‐subjects). None of the 21OHAb+ subjects had metabolic or clinical signs of adrenal dysfunction. HLA‐DRB1*03‐DQA1*0501‐DQB1*0201 (DR3‐DQ2) was significantly more frequent in GAD65Ab+ subjects than in healthy controls (OR = 5.42, corrected P < 0.0026). The presence of TPOAb was significantly associated with DR3‐DQ2 (P = 0.024).

CONCLUSIONS

Our study demonstrates that the presence of GAD65Ab identifies a subgroup of type 2 diabetic patients with high risk for thyroid and adrenal autoimmunity, and that both GAD65Ab and TPOAb are associated with the presence of HLA‐DR3‐DQ2, in these patients.
The use of insulin‐like growth factor 1 reference values for the diagnosis of growth hormone deficiency in prepubertal children
Authors: Bussières Laurence , Souberbielle Jean‐Claude , Pinto Graziella , Adan Luis , Noel Michele , Brauner Raja
Published: March 2003

OBJECTIVE

This study was done to determine whether the use of reference values obtained in children with idiopathic short stature (ISS) improved the clinical value of serum insulin‐like growth factor I (IGF‐1) as a tool for diagnosing GH deficiency (GHD) in prepubertal children.

PATIENTS AND METHODS

Serum IGF‐1 was measured with a new IRMA kit (IGFI‐RIA CT, Cis Bio, Gif sur Yvette, France) in 168 prepubertal normal children and in prepubertal children with ISS (n = 68), organic GHD due to a craniopharyngioma (oGHD, n = 15) and permanent idiopathic GHD (iGHD, n = 28).

RESULTS

IGF‐1 was lower (P < 0.001) in iGHD than in either ISS or oGHD and was below the fifth percentile of the normal range in 29/68 ISS (43%), 8/15 oGHD (53%) and 28/28 (100%) iGHD patients. Three oGHD (20%) and two iGHD (7%) patients had a serum IGF‐1 below the fifth percentile of the normal group but above the fifth percentile of the ISS group. Thus, a serum IGF‐1 below the fifth percentile of the normal group distinguished between normal children and iGHD with 100% sensitivity, between normal and oGHD with 53% sensitivity and between normal and all GHD (idiopathic + organic) with 84% sensitivity; the overall specificity was only 57%. Conversely, a serum IGF‐1 below the fifth percentile of the ISS population distinguished between ISS and iGHD with 93% sensitivity, between ISS and oGHD with 33% sensitivity and between ISS and all GHD with 72% sensitivity; the overall specificity was then 95%.

CONCLUSIONS

A serum IGF‐1 within the normal range virtually excludes idiopathic GHD but does not rule out organic GHD, whereas an IGF‐1 below the ISS range is strongly in favour of GHD, after exclusion of poor nutritional status and/or liver disease. An IGF‐1 below the normal range but in the idiopathic short stature range gives no definitive conclusion even when it is associated with a low GH peak. Thus, whereas reference values obtained in normal children must be used to interpret serum IGF‐1 in short prepubertal children, reference data obtained in idiopathic short stature children should also be taken into account.
Oral glucose tolerance testing but not intravenous glucose administration uncovers hyper‐responsiveness of hypothalamo–pituitary–adrenal axis in patients with adrenal incidentalomas
Authors: Beuschlein F. , Borgemeister M. , Schirra J. , Göke B. , Fassnacht M. , Arlt W. , Allolio B. , Reincke M.
Published: March 2003

OBJECTIVE

Modern imaging techniques are detecting adrenal incidentalomas with increasing frequency. Recent data suggests food‐dependent hypercortisolism in a subgroup of patients with bilateral macronodular hyperplasia due to aberrant adrenal responsiveness to gastric inhibitory polypeptide (GIP). We studied the putative influence of food intake on the hypothalamo–pituitary–adrenal (HPA) axis in patients with adrenal incidentalomas and possible mediation by GIP.

PATIENTS AND MEASUREMENTS

We examined 15 mildly obese patients with adrenal incidentalomas, eight healthy, lean subjects, and seven obese patients with the metabolic syndrome, who were matched for body weight and age. Each individual underwent oral glucose tolerance testing (OGTT, 75 g glucose), i.v. glucose administration (IVGTT, 30 g glucose over 1 h) and i.v. glucose plus GIP infusion (body weight adapted leading to physiological postprandial GIP serum levels) on three occasions. Plasma glucose, ACTH and cortisol were measured from blood samples taken every 15 minutes from time − 30 minutes to + 75 minutes.

RESULTS

OGTT, i.v. glucose administration and GIP infusion led to comparable glucose values within the groups. In contrast to normal subjects and patients with the metabolic syndrome, patients with adrenal incidentalomas had significantly higher mean cortisol values after oral glucose intake as compared to i.v. glucose administration or GIP infusion. The increase in cortisol levels was preceded by a corresponding ACTH increase. No significant effect of GIP administration on cortisol or on ACTH secretion could be detected.

CONCLUSIONS

Patients with adrenal incidentalomas showed an abnormal responsiveness of the pituitary–adrenal axis to oral glucose administration. The cortisol peaks in these patients seemed to be ACTH‐mediated and were not induced by GIP.
Oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease
Authors: Gebre‐Medhin Gennet , Husebye Eystein S. , Mallmin Hans , Helström Lotti , Berne Christian , Karlsson F. Anders , Kämpe Olle
Published: March 2003

OBJECTIVE

Patients with primary adrenocortical failure (Addison's disease) have abnormally low levels of DHEA and androgens relative to age. To define a suitable dose, the effect of oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease (n = 9) was evaluated.

DESIGN AND MEASUREMENTS

DHEA was administered as a daily oral dose of either 50 mg (n = 5) or 200 mg (n = 4). Blood sampling and measurements of insulin sensitivity (as measured with euglycemic insulin clamp technique) and body composition (as measured by dual energy X‐ray absorptiometry) were performed before and during DHEA treatment and at a 3‐month follow up.

RESULTS

DHEA and DHEA(S) levels were restored to normal in those patients receiving 50 mg whereas DHEA(S) level was slightly above the normal reference value in those receiving 200 mg. Circulating levels of androgens (androstenedione, testosterone and testosterone/SHBG ratio) were normalized in all patients. A slight rise in IGF‐1 levels was seen in both groups as was a decrease in the levels of low and high density lipoproteins. No effect on blood glucose levels or insulin sensitivity was seen and no change of body composition was observed. No serious side‐effects were seen, but some of the patients experienced increased apocrine sweat secretion (n = 7), itchy scalp (n = 2) and acne (n = 7), all of which were reversed when DHEA was discontinued.

CONCLUSION

A daily replacement dose of 50 mg of DHEA results in near physiological levels of DHEA, DHEA(S) androstenedione and testosterone in women with Addison's disease, without severe side‐effects.
Concurrent secretion of aldosterone and cortisol from an adrenal adenoma — value of MRI in diagnosis
Authors: Allan Carolyn A. , Kaltsas Gregory , Perry Les , Lowe David G. , Reznek Rodney , Carmichael David , Monson John P.
Published: March 2003

A 43‐year‐old female with a 24‐years history of hypertension presented for further investigation and management of primary hyperaldosternoism. Postural studies were not conclusive and magnetic resonance (MR) imaging demonstrated a 27 × 18 mm lesion of the right adrenal gland which showed no signal loss during in and out of phase imaging. Although these appearances were considered to be atypical of those seen on MR in patients with aldosterone producing adrenal adenomas the patient underwent an adrenalectomy with removal of a 3 × 3 × 2 cm right adrenal mass. Post‐operatively she became hypotensive and a 0900 hours serum cortisol was undetectable (< 50 nmol/l), consistent with adrenal insufficiency. Following the administration of hydrocortisone there was normalization of the blood pressure and subsequent adrenal stimulation tests confirmed the presence of functioning adrenal tissue albeit with an inadequate response. Cortisol measurement from preoperative samples revealed loss of normal diurnal rhythm whereas DHEAS levels both pre and postoperatively were undetectable, consistent with ACTH supression resulting from autonomous cortisol secretion in addition to aldosterone. Concurrent secretion of cortisol should always be considered in Conn's adenomas particularly when atypical radiological features are present.
Influence of exogenous melatonin on catecholamine levels in postmenopausal women prior and during oestradiol replacement
Authors: Cagnacci Angelo , Zanni Anna Lisa , Veneri Maria Grazia , Menozzi Renata , Volpe Annibale , Rio Graziano Del
Published: March 2003

OBJECTIVE

In young individuals melatonin administration reduces circulating norepinephrine. Some effects of melatonin are reduced in elderly women and are modulated by gonadal steroids. Accordingly, the influence of melatonin on catecholamine levels was investigated in postmenopausal women without and with oestradiol replacement.

DESIGN

Prior to and after 2 months of transdermal oestradiol (50 μg/day), women were studied on two consecutive days, on which they received placebo or 1 mg of melatonin orally in a randomised and double‐blind fashion.

PATIENTS

Fourteen healthy postmenopausal women.

MEASUREMENTS

Resting levels of epinephrine and norepinephrine and their responses to both a cold stimulus, performed by placing a hand in a basin of water and ice for 2 minutes, and to 10 minutes of upright position (upright test).

RESULTS

Prior to oestradiol, melatonin did not modify baseline or stimulated catecholamine levels. In contrast, during oestradiol, melatonin tended to reduce, although not significantly, baseline norepinephrine levels (P = 0.053), and significantly reduced peak values (P = 0.0061) and integrated norepinephrine response (P = 0.0076) to the cold stimulus. Responses of norepinephrine to the upright test were not modified, while those of epinephrine were increased (P = 0.042). During, but not prior to oestradiol replacement, modifications induced by melatonin (melatonin day‐placebo day) in the norepinephrine response to the cold (r 2 = 0.457; P = 0.0079) and the upright (r2 = 0.747; P = 0.0001) tests were linearly and inversely related to the responses of the placebo day.

CONCLUSIONS

Melatonin does not modulate adrenergic activity in postmenopausal women without hormone replacement therapy. Oestradiol replacement restores the capability of melatonin to modulate adrenergic activity, particularly the norepinephrine response to stimuli.
Body proportions during 6 years of GH treatment in children with short stature born small for gestational age participating in a randomised, double‐blind, dose–response trial*
Authors: Sas Theo C. J. , Gerver Willem‐Jan M. , De Bruin Rob , Mulder Paul G. H. , Cole Tim J. , De Waal Wouter , Hokken‐Koelega Anita C. S.
Published: March 2003

The aim of this study was to assess body proportions in children with short stature born small for gestational age (SGA) before and during 6 years of growth hormone (GH) treatment.

A prospective randomised double‐blind dose–response study comparing the effects of 3 vs. 6 IU GH/m2/day.

Seventy‐nine children with short stature (height SD‐score < −1·88) born small for gestational age (birth length SD‐score < −1·88).

Before and during GH treatment, height, sitting height (SH), hand (Hand) and foot length (Foot), biacromial (Biac) and biiliacal diameter (Biil) were measured. All results were adjusted for age and sex, and expressed as SD‐scores (SDS) using reference values for healthy Dutch children. To describe the size of SH, Hand, Foot, Biac, and Biil in relation to height, these values were adjusted for the SDS of height.

At baseline, these short children had small hands and feet and narrow shoulders and pelvis compared to healthy peers. Height and SH, were, however, even more affected. Consequently, on average, these children had relatively large hands and feet, and relatively broad shoulders and pelvis compared to their height, but a normal sitting height in proportion to height. In most of the individuals, the values for body proportions were, however, within the normal range. During 6 years of GH treatment the SD‐scores of all measurements increased significantly towards values more close to zero. The mean size of Hand, Foot, and Biil decreased in proportion to height. The mean SH increased relatively more than height, however, to values well within the normal range. The mean Biac in relation to height had not changed after 6 years of GH treatment. No differences in the 6‐year changes in body proportions were found between the two GH dosage groups.

Untreated short children born small for gestational age have, on average, relatively large hands and feet, and broad shoulders and pelvis, but a normal sitting height compared to height. The increase in height during 6 years of GH treatment is accompanied by an improvement of the proportions of the size of hands, feet, and biiliacal diameter, in relation to height. The increase in height appeared to be the result of the increase in sitting height as well as leg length, but the sitting height SD‐score increased slightly more than that of leg length. The changes in body proportion during GH treatment were dose‐independent. Thus, 6‐year continuous GH treatment with either 3 or 6 IU/m2/day in children with short stature born small for gestational age does not negatively influence body proportions.