bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory action on GHRH‐induced GH secretion of chronic tamoxifen treatment in breast cancer
Authors: De Marinis  , Mancini  , Izzi  , Bianchi  , Giampietro  , Fusco  , Liberale  , Rossi  , Valle
Published: March 2003

OBJECTIVE

Previous in vitro and in vivo studies on animal models have demonstrated that tamoxifen (TAM) inhibits GH secretion. Studies in humans are conflicting. The aim of this study was to evaluate the effect of chronic TAM treatment on GH secretory dynamics in the presence of negligible endogenous oestrogens, in postmenopausal women with breast cancer.

PATIENTS

Ten female patients were studied over a 6–12‐month period after surgical therapy, before medical therapy, and during chronic treatment with TAM (20 mg/day p.o.).

MEASUREMENTS

In all subjects we performed a standard GHRH‐test (50 mg i.v. as a bolus) and compared the single time points, the peak response and the areas under the curves (AUC), before and during treatment. In basal samples, we evaluated the circulating levels of IGF‐1, IGF‐BP3 and their ratio, SHBG, FSH, LH, Oestradiol (E2) and PRL. GH was assayed by Immunoradiometric assay (IRMA). Insulin‐like growth factor type I (IGF‐I), Insulin‐like growth factor‐binding protein‐3 (IGF‐BP3), FSH, LH and PRL were measured by Radioimmunoassay (RIA). SHBG was measured by a noncompetitive liquid phase immunoradiometric assay, while E2 was measured directly in plasma by a liquid phase technique.

RESULTS

TAM chronic treatment significantly reduced GH response to GHRH at single time point evaluations, GH peak response (mean decrease: 59.8 ± 7.3%) and GH‐AUC (mean decrease 53.8 ± 8.9%). TAM also significantly reduced plasma IGF‐1 levels. No significant variations were found in IGF‐BP3 levels or in the IGF‐1/IGF‐BP3 ratio. A significant inverse correlation between SHBG and IGF‐1 circulating levels was noticed during TAM treatment.

CONCLUSIONS

Our data show that long‐term tamoxifen treatment blocks the response of GH to exogenous GHRH and reduces IGF‐1 levels, possibly by a central mechanism other than the demonstrated peripheral action. The results of this study, keeping in mind the demonstrated mitogenic role of IGF‐1 in cancer proliferation, can contribute to clarify the mechanism by which TAM exerts its antiproliferative effect.
The combined pituitary function test in children: an evaluation of the clinical usefulness of TRH and LHRH stimulation tests through a retrospective analysis of one hundred and twenty six cases
Authors: Westwood  , Butler  , McLellan  , Barth
Published: March 2003

OBJECTIVE

The combined pituitary function test is routinely used in the endocrine investigation of short children. The TRH and luteinising hormone‐releasing hormone (LHRH) response tests have been shown to be of minimal value in adults. We have evaluated the clinical utility of these tests in the context of combined pituitary function testing in children.

DESIGN

A retrospective analysis of basal hormone measurements and pituitary stimulation tests in relation to clinical assessment of pituitary function.

PATIENTS

One hundred and twenty‐six children, 82 boys and 44 girls, aged 2–17 years, who had undergone pituitary function testing were studied.

RESULTS

The TSH response to TRH stimulation correlated directly with basal plasma TSH but not basal plasma total T4. In patients with an impaired response to stimulation, basal TSH concentrations were <2.0 mIU/l and significantly lower than in patients with a normal response (P < 0.0001). An impaired response to TRH stimulation had a positive predictive value of 0.43 and a negative predictive value of 0.90 for the diagnosis of hypopituitarism. A basal TSH concentration of <2.0 mIU/l had a positive predictive value of 0.22 and a negative predictive value of 0.92. A low basal T4 (normal range 60–140 nmol/l) in combination with an inappropriately low or normal basal TSH was always associated with a diagnosis of hypopituitarism.

The responses of plasma LH and FSH to LHRH stimulation correlated directly with basal plasma LH and FSH concentrations. Basal gonadotrophin concentrations, basal sex hormone concentrations or response to LHRH stimulation could not distinguish patients with constitutional delay of growth and puberty from those with hypopituitarism. There was no apparent relationship between either basal gonadotrophin concentrations or response to LHRH stimulation and clinical assessment of pituitary function. In patients ≥13 years with constitutional delay of growth and puberty the median and interquartile ranges of basal LH and FSH were 1.4 IU/l (0.7–3.6) and 2.6 IU/l (2.2–5.2) respectively. The three hypopituitary patients in this study with chronological age ≥13 years had undetectable concentrations of both gonadotrophins. The response of LH and FSH to LHRH stimulation was significantly lower in patients ≥13 years with clinical hypopituitarism than in those with intact pituitary function (P <0.02).

CONCLUSION

TRH and LHRH tests in children with short stature appear to have little value over and above the baseline hormone measurements. An abnormal response to hormone stimulation is not diagnostic of hypothalamic‐pituitary disease. We have demonstrated that neither TRH nor LHRH stimulation tests should be routinely used in the investigation of children with short stature.
Effects of normalization of GH hypersecretion on lipoprotein(a) and other lipoprotein serum levels in acromegaly
Authors: Maldonado Castro Gonzalo F. , Escobar‐Morreale Héctor F. , Ortega Henar , Gómez‐Coronado Diego , Balsa Barro José A. , Varela César , Lasunción Miguel A.
Published: March 2003

BACKGROUND & AIMS

Lipoprotein(a) has been recognized as an important risk factor for cardiovascular disease. Lipoprotein(a) has been found to be elevated in sera of acromegalic patients, possibly contributing to the increased incidence of coronary heart disease found in these patients. In the present study we sought to determine the effects of GH hormonal status on lipoprotein(a) and other lipid parameters, including lipoprotein lipase (LPL) activity.

DESIGN

Cross‐sectional study.

PATIENTS

Twenty acromegalic patients, with either active (n = 12) or controlled (n = 8) acromegaly, were studied. Twenty‐nine healthy subjects served as control group for serum lipid measurements.

MEASUREMENTS

Serum GH, IGF‐1, IGF binding protein‐3 (IGFBP‐3) and insulin levels were measured in patients. Insulin resistance was measured by the homeostatic model assessment (HOMA). Plasma total cholesterol, triglycerides, HDL‐lipids, apolipoproteins A‐I and B, lipoprotein(a) and lipoprotein lipase activity were also measured.

RESULTS

The highest lipoprotein(a) levels were observed in patients with active acromegaly, followed by patients with controlled acromegaly, whose lipoprotein(a) concentrations were still significantly higher than those of the control group (means ± SEM: active acromegaly, 0.67 ± 0.13 g/l; controlled acromegaly, 0.41 ± 0.12 g/l; controls 0.17 ± 0.02 g/l; P < 0.05). There were no differences in other lipid and lipoprotein values among the groups. In patients, significant correlations were observed between lipoprotein(a) and basal GH levels (r = 0.56, P < 0.02), mean GH levels (r = 0.48, P < 0.05) and with insulin resistance estimated by HOMA (r = 0.62, P < 0.01). No correlations were found between lipoprotein(a) and IGF‐1 or IGFBP‐3 levels.

CONCLUSIONS

Our present results demonstrate that both active acromegalic patients and those with controlled disease have elevated serum lipoprotein(a) concentrations. The findings might suggest that the present biochemical criteria for cure of acromegaly are not strict enough to result in the normalization of all the undesirable metabolic changes found in this disease, and also that significant cardiovascular risk may persist despite successful treatment of acromegaly.
Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function
Authors: Kamischke Axel , Diebäcker Julia , Nieschlag Eberhard
Published: March 2003

OBJECTIVE

Gestagens are known to suppress gonadotrophins in women and are currently also under investigation for the development of hormonal male contraceptives. The aim of the study was to assess the potential of norethisterone enanthate (NETE) for male contraception.

DESIGN AND MEASUREMENTS

The suppressive effect of a single injection of 200 mg NETE on serum gonadotrophins, serum testosterone, lipids, spermatogenesis, well‐being and sexual function was evaluated in seven healthy men.

RESULTS

In this single dose study treatment was well tolerated by all volunteers. NETE led to a rapid, profound and significant suppression of serum LH (day 6 − day 10), FSH (day 2 − day 29), testosterone (day 1 − day 29 and day 35) and SHBG (day 6 − day 35). At study end sperm counts were significantly suppressed. Numbers of spontaneous erections (day 17, 23 and 26), number of sexual fantasies (day 20 and 23) as well as libido (day 20 and 26) were significantly decreased compared to baseline. All other parameters including lipids, augmented glucose, testicular volume and well‐being showed no significant alterations.

CONCLUSION

Because of its strong, rapid and sustained suppression of serum FSH and testosterone norethisterone enanthate offers great potential for hormonal male contraception if combined with testosterone esters.
Functional characterization of five constitutively activating thyrotrophin receptor mutations
Authors: Wonerow Peter , Chey Soroth , Führer Dagmar , Holzapfel Hans‐Peter , Paschke Ralf
Published: March 2003

OBJECTIVE

Gain of function mutations of the thyrotrophin receptor (TSHR) affect several functional characteristics, such as cAMP and inositol phosphate (IP) accumulation, cell surface expression and TSH affinity. In this study we compared five constitutively activating TSHR mutations, four receptors with a point mutation (S505N, L629F, I630L, V656F) and a nine amino acid (aa) deletion mutant (aa positions 613–621) for these functional parameters in parallel transfection experiments.

METHODS

The wild‐type TSHR (wt) and TSHRs containing the mutations S505N, L629F, I630L, V656F and the deletion 613–621 (all cloned in the expression vector pSVL) were transiently expressed in COS‐7 cells in parallel experiments. Forty‐eight hours after transfection the basal and stimulated cAMP and inositol phosphate accumulation as well as the cell surface expression (by FACS and ELISA), KD‐values and TSHR down regulation by different stimuli were determined.

RESULTS

In contrast to the very different values for specific constitutive activity (sca) (ranging from 7.5 to 100.3‐fold wt) and very different levels of receptor cell surface expression (11–94% wt level) the basal cAMP accumulation determined in transfected COS‐7 cells was surprisingly uniform (6.5–8.0 over wt basal). None of the point mutated receptors constitutively activates the phospholipase C cascade. In contrast the deletion 613–621 mutant showed constitutive activity for the IP pathway with a twofold increase in basal IP accumulation compared to the wild type TSHR. All investigated TSHR‐mutants showed a TSH‐stimulated receptor down‐regulation, which seems to be independent of the phospholipase C pathway.

CONCLUSIONS

The uniform basal cAMP values in spite of the large variation in specific constitutive activity values suggest that the COS‐7 cell overexpression system used for the in vitro characterization is partly regulated. This regulation is most likely due to receptor down regulation. The TSHR deletion mutant (613–621) showed a constitutive activity for both the Gαs and the Gαq/11 pathways. The TSH‐mediated IP‐stimulation by this mutant contrasts with its unresponsiveness to TSH for cAMP accumulation and therefore supports the model of different active conformations of the TSHR.
Monosomy of chromosome 11 in pituitary adenoma in a patient with familial multiple endocrine neoplasia type 1
Authors: Kontogeorgos G. , Kapranos N. , Tzavara I. , Thalassinos N. , Rologis D.
Published: March 2003

Multiple endocrine neoplasia type 1 (MEN 1) represents an endocrine syndrome characterized by complex pituitary, parathyroid and pancreatic neoplasia. Loss of heterozygosity of the specific region 11q13 has been reported in several tumours from patients with MEN 1 inherited disorder. We present a case of a young patient with familial MEN 1 syndrome with a pituitary adenoma exhibiting monosomy of chromosome 11. The patient presented with a large and rapidly growing pituitary adenoma associated with markedly elevated serum PRL levels, progressive bilateral visual loss and hydrocephalus. The resected adenoma was chromophobic, mainly PRL‐producing and to a lesser degree immunoreactive for GH. Fluorescence in situ hybridization (FISH) using an α‐satellite centromeric probe detected loss of one chromosome 11 copy in almost all pituitary adenoma cells. Clinical and biochemical studies revealed parathyroid hyperplasia and MRI studies detected a pancreatic tumour in addition to the pituitary adenoma. To our knowledge this is the first study reporting monosomy 11 in pituitary adenoma in a patient associated with familial MEN 1 syndrome.
Recurrent ACTH‐independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone
Authors: Hána V. , Dokoupilová M. , Marek J. , Plavka R.
Published: March 2003

A 17‐year‐old primigravid woman presented with Cushing's syndrome. Typical clinical symptoms and signs developed at the beginning of pregnancy. By week 17 of gestation, plasma cortisol diurnal rhythm was absent and there was a paradoxical increase in plasma cortisol after a 1‐mg dexamethasone overnight suppression test. Basal urinary free cortisol was 10 times above the upper limit (in pregnancy) and ACTH levels were suppressed. The diagnosis of ACTH – independent Cushing's syndrome was established. MRI scans revealed normal adrenal and pituitary glands. To control hypercortisolism, the patient was treated with metyrapone. At 34 weeks of gestation, the patient developed preeclampsia and underwent caesarean section. A female infant weighing 1070 g was delivered. No apparent metyrapone‐induced teratogenic effects were observed. Cushing's syndrome in the patient resolved within three weeks of delivery. No corticosteroid replacement therapy either for child or mother was needed. Eight months after delivery the patient became pregnant again and rapidly developed Cushing's syndrome with typical clinical symptoms and signs and laboratory results (urinary free cortisol 6464 nmol/24 h). This second pregnancy was unwanted and terminated by artificial abortion that was followed by rapid resolution of hypercortisolism. A third pregnancy, 12 months after delivery was also accompanied by the rapid development of hypercortisolism which recovered after artificial termination.

The mechanisms by which pregnancy‐induced Cushing's syndrome occurred in this patient are unclear. Aberrant responsiveness or hyperresponsiveness of adrenocortical cells to a non‐ACTH and non‐CRH substance produced in excess in pregnancy should be considered.

Metyrapone suppression of hypercortisolism currently represents the best treatment for these rare cases.
In vivo secretory potential and the effect of combination therapy with octreotide and cabergoline in patients with clinically non‐functioning pituitary adenomas
Authors: Andersen Marianne , Bjerre Per , Schrøder Henrik D. , Edal Anette , Høilund‐Carlsen Poul F. , Pedersen Per Hyltoft , Hagen Claus
Published: March 2003

The secretory capacity, in vivo, of clinically non‐functioning pituitary adenomas may possibly predict tumour volume reduction during intensive medical therapy.

Ten patients (mean (range) 53 years (26–73)) with clinically non‐functioning macroadenomas, ≥ 10 mm were studied. The secretory capacity of the adenomas was examined using basal, NaCl and TRH‐stimulated LH, FSH and α‐subunit levels. The effect on tumour volume of 6 months' therapy with the combination of a somatostatin analogue, octreotide 200 µg × 3/day and a dopamine‐D2‐agonist, cabergoline 0·5 mg × 1/day was studied. The basal LH, FSH and α‐subunit levels were determined before and during 6 months' therapy with octreotide and cabergoline, and MR scans were used to evaluate tumour volume before and during this period of therapy. Octopus‐perimetry was used to examine the visual fields.

A reduction in tumour volume (mean ± SEM (range); 30% ± 4% (18–46%)) during 6 months of combination therapy with octreotide and cabergoline was recorded only in patients with in vivo secretory potential. Tumour volume was not reduced in four patients: in three of these patients it remained unchanged while in one patient it was observed to have increased (by 14%). Of the six patients with pretherapy secretory capacity, one displayed a very high basal level of α‐subunit (74 µg/l) despite unmeasurable levels of LH and TSH, and an FSH‐level of 1 IU/l. The other five patients presented paradoxical LH, FSH and/or α‐subunit responses to TRH. A reduction in basal levels of LH, FSH and/or α‐subunit was observed in all six patients, and the maximum reduction of at least one of the hormonal levels was 66% ± 7% (50–98%). The basal levels of LH, FSH and α‐subunit in the 10 patients were (mean ± SEM (range)), 3·0 IU/l ± 1·0 (0·0–7·4), 12·7 IU/l ± 5·0 (0·0–39·0) and 9·0 IU/l ± 7·0 (0·2–74·0). During six months of therapy with octreotide and cabergoline, the basal levels of LH, FSH and α‐subunit were reduced by ≥ 50% in seven patients – including the six patients with in vivo secretion prior to therapy. No new visual field defects were detected during therapy and no deterioration of existing visual field defects was recorded. The medical therapy was well tolerated.

The in vivo basal and TRH‐stimulated secretory capacity of LH, FSH and α‐subunit predicted tumour reduction following intensive medical therapy in all of our patients with non‐functioning pituitary adenomas.
A chimeric CYP11B1/CYP11B2 gene in glucocorticoid‐insuppressible familial hyperaldosteronism
Authors: Ise Takuyuki , Shimoda Atsushi , Takakuwa Hiroshi , Kato Tamayo , Izumiya Yoshiaki , Shimizu Kazuaki , Suzuki Takashi , Sasano Hironobu , Yokoyama Hitoshi , Kobayashi Kenichi
Published: March 2003

Although a chimeric gene combining the 11β‐hydroxylase gene (CYP11B1) and the aldosterone synthase gene (CYP11B2) explains the pathophysiology of familial hyperaldosteronism (FH) type I, the contribution of this abnormality to FH type II has not been tested. We screened genomic DNA from a Japanese family with FH type II for the CYP11B1/CYP11B2 gene. The index patient was a 27‐year‐old woman with hypertension. Hypokalaemia, elevated plasma aldosterone and suppressed plasma renin activity suggested primary aldosteronism. Though computed tomography failed to reveal an adrenal tumour, left adrenalectomy was indicated due to a high aldosterone concentration in left adrenal venous blood. The resected adrenal gland contained an adenoma. As her mother had also been diagnosed with primary aldosteronism due to an adenoma, we administered oral dexamethasone to our patient before the operation and observed the response of the blood pressure and plasma aldosterone concentration for 2 weeks. Both parameters remained elevated during the treatment period, confirming the diagnosis of FH type II. Total DNA was isolated from blood cells of the index patient, her mother, and an unaffected brother. Samples were amplified by polymerase chain reaction using specific primers from CYP11B1 and CYP11B2. Unique DNA fragments of 1·4 kb were obtained from the index patient and her mother, but not from the healthy subject. The CYP11B1/CYP11B2 chimeric gene was found in a Japanese family with FH type II.
Frequency of appearance of myeloperoxidase‐antineutrophil cytoplasmic antibody (MPO‐ANCA) in Graves' disease patients treated with propylthiouracil and the relationship between MPO‐ANCA and clinical manifestations
Authors: Noh Jaeduk Yoshimura , Asari Tomoki , Hamada Noboru , Makino Fuminori , Ishikawa Naofumi , Abe Yoshifumi , Ito Koichi , Ito Kunihiko
Published: March 2003

OBJECTIVE Myeloperoxidase antineutrophil cytoplasmic antibody (MPO‐ANCA)‐positive vasculitis has been reported in patients with Graves' disease who were treated with propylthiouracil (PTU). The appearance of MPO‐ANCA in these cases was suspected of being related to PTU because the titres of MPO‐ANCA decreased when PTU was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO‐ANCA and vasculitis during PTU therapy, or on the incidence of MPO‐ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease.

PATIENTS We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO‐ANCA, and for the development vasculitis after starting PTU therapy. Twenty‐nine of them were later excluded because of adverse effects of PTU or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23·6 months (range: 3–37 months).

MEASUREMENTS MPO‐ANCA was measured at intervals of 2–6 months.

RESULTS Before treatment, the MPO‐ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4·1%) of the 73 patients were positive for MPO‐ANCA at 13, 16 and 17 months, respectively, after the start of PTU therapy. In two of them, the MPO‐ANCA titres transiently increased to 12·8 and 15·0 U/ml, respectively, despite continued PTU therapy, but no vasculitic disorders developed. In the third patient, the MPO‐ANCA titre increased to 204 U/ml and she developed a higher fever, oral ulcers and polyarthralgia, but the symptoms resolved 2 weeks after stopping PTU therapy, and the MPO‐ANCA titre decreased to 20·7 U/ml by 4 months after discontinuing PTU.

CONCLUSIONS PTU therapy may be related to the appearance of MPO‐ANCA, but MPO‐ANCA does not appear to be closely related to vasculitis.
An audit of management of differentiated thyroid cancer in specialist and non‐specialist clinic settings
Authors: Kumar H. , Daykin J. , Holder R. , Watkinson J.C. , Sheppard M.C. , Franklyn J.A.
Published: March 2003

OBJECTIVE Thyroid cancer is the most common endocrine malignancy but is none the less rare. Some aspects of its management remain controversial. Previous audits of patient management in the United Kingdom have revealed deficiencies, especially in communication between specialists. We have audited patient management in a large university‐associated teaching hospital, assessing points of good practice identified from published guidelines and reviews, and have compared findings in groups of patients managed jointly by specialists with an interest in thyroid cancer (including surgeon, endocrinologist and oncologist) with a group managed by other clinicians outside that setting.

DESIGN AND PATIENTS Retrospective case‐note review of 205 patients with differentiated (papillary or follicular) cancer including group A (n = 134; managed in a specialist multi‐disciplinary clinic setting) and group B (n = 71; managed in other clinic settings). Points of good practice investigated were adequacy of surgery, surgical complications, prescription and adequacy of T4 treatment, adequacy of monitoring by measurement of serum thyroglobulin and action taken and appropriate administration of ablative radioiodine.

RESULTS Deficiencies in management of the cohort as a whole were identified, including inadequate surgery and inadequate TSH suppression in approximately one‐fifth of the cases. Monitoring with thyroglobulin measurements and action when serum thyroglobulin was high were also inadequate in some cases and ablative radioiodine was not given, despite being indicated in 11·7% of the cohort. Inadequate surgery and failure to administer radioiodine were less common in those managed in a specialist clinic setting than in those managed in other clinic settings.

CONCLUSIONS The findings highlight the need for locally agreed protocols in managing relatively rare endocrine disorders such as thyroid cancer and argue in favour of centralization of expertise and patient management in multi‐disciplinary specialist clinic settings.
Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance
Authors: Ruiz Mini , Lind Ulrika , Gåfvels Mats , Eggertsen Gösta , Carlstedt‐Duke Jan , Nilsson Lennart , Holtmann Martin , Stierna Pontus , Wikström Ann‐Charlotte , Werner Sigbritt
Published: March 2003

OBJECTIVE Primary glucocorticoid resistance is characterized by decreased sensitivity to cortisol signalling. We have performed genetic analysis of the glucocorticoid receptor (GR) gene in 12 unrelated patients with primary cortisol resistance as defined by a pathological dexamethasone suppression test.

METHODS Exon specific polymerase chain reaction amplification of the GR gene and sequencing of each exon was carried out. The two mutations were characterized in vitro in terms of glucocorticoid driven reporter gene activity in a transient transfection assay and in a ligand binding assay. Molecular modelling of the R477H mutant was performed based on the X‐ray structure of the GR‐DNA binding domain.

RESULTS Two novel mutations in the GR gene were found: R477H in the DNA‐binding domain which is the first reported mutation in that region of the human GR gene and G679S in the ligand binding domain. The R477H mutation showed no transactivating capacity, whereas the G679S mutation had reduced transactivation capacity compared to the wild‐type (wt) GR. When tested for ligand binding capacity, the G679S mutation had 50% binding affinity compared to the wt GR. The effect of the point mutation R477H was deduced by a comparison between the wt structure and the model of the mutant. The wt GR has direct and water mediated contact with the phosphate groups of the glucocorticoid responsive element (GRE) whereas, in the model, the mutation R477H has no contact with the GRE. The G679S mutation is located on the surface of the ligand binding domain, at a distance from the steroid‐binding site. A previously reported polymorphism, AAT to AAC at amino acid position 766, was found in four of the patients.

CONCLUSIONS In two of 12 patients with clinical glucocorticoid resistance, mutant forms of GR could be found. The glucocorticoid resistance in vivo in these two patients corresponds to impaired function of the two mutated GR forms in two in vitro assays. The relevance of the conservative polymorphism for the glucocorticoid insensitivity noted in these patients remains to be clarified.
Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma
Authors: Franc S. , Niccoli‐Sire P. , Cohen R. , Bardet S. , Maes B. , Murat A. , Krivitzky A. , Modigliani E. , Medullary Study Group (getc) The French
Published: March 2003

BACKGROUND Medullary thyroid carcinoma is a rare tumour derived from the thyroid parafollicular calcitonin‐secreting cells. Calcitonin is a very specific marker of this cancer that allows preoperative diagnosis. Serum calcitonin assay is particularly useful to define the postoperative state of patients (cured, apparently cured, not cured) and, because of its great sensitivity, it has a major place in the postoperative follow‐up.

OBJECTIVE To identify, among patients thyroidectomized for medullary thyroid carcinoma (MTC), the characteristics of authentic recurrent MTC [re‐elevation of stimulated serum calcitonin (CT) level measured by a sensitive immunoradiometric assay, after postoperative normalization].

PATIENTS AND METHODS We first collected, through the national registry of the French Calcitonin Tumour Study Group (GETC), patients who had undergone a total thyroidectomy with or without lymph node surgery and who were not cured at the last follow‐up visit. Among 453 such patients included in the database, 15 patients met the criteria for authentic recurrence as defined in previous studies: they had been first considered as cured during the 6 months following the initial surgical procedure (basal and pentagastrin‐stimulated serum calcitonin level ≤ 10 ng/l) but had a secondary rerise of their pentagastrin‐stimulated calcitonin level, over 10 ng/l. Eight of them even had an undetectable (< 2 ng/l) immediate postoperative CT, confirming the initial postoperative cure. The characteristics (age, nature of disease, stage at surgery and type of node dissection) of these 15 patients were studied.

RESULTS According to the Tumour Node Metastasis classification, nine patients were T1 and, among them, five patients had had complete lymph node surgery without any evidence of nodal metastases (N0). The recurrence was 3·2 ± 2·2 years (range: 0·7–7·5) after the initial surgery.

CONCLUSIONS 3·3% of patients not cured at the last visit had a recurrent MTC. This recurrence occurred whatever the stage, and even if the primary surgery for MTC was a priori complete. These results emphasize the need for a regular biochemical follow‐up because recurrence may appear many years after the initial surgery.
Effect of Sandostatin® LAR® on sleep apnoea in acromegaly: correlation with computerized tomographic cephalometry and hormonal activity
Authors: Ip M. S. M. , Tan K. C. B. , Peh W. C. G. , Lam K. S. L.
Published: March 2003

OBJECTIVES Sleep apnoea has been reported to occur in subjects with acromegaly. This study evaluates the relationship among biochemical activity, sleep apnoeic activity and upper airway anatomic profile in acromegaly, and the effect of Sandostatin® LAR®, a long‐acting somatostatin analogue, on these parameters.

PATIENTS Fourteen subjects with acromegaly were recruited.

MEASUREMENTS Subjects were assessed at baseline and those with apnoea‐hypopnoea index (AHI) ≥ 5 were reassessed after 6 months of treatment with Sandostatin® LAR® 20–30 mg IMI 4‐weekly. Biochemical activity was assessed with levels of GH and IGF‐1. Sleep disordered breathing was assessed with overnight polysomnography. Upper airway anatomic profile was defined with computerized tomographic cephalometry.

RESULTS Of 14 subjects (age 42·0 ± 8·1 years, mean ± SD; 11 men) at baseline, there was a positive correlation between GH and tongue length (VT; P = 0·004), and between AHI and cephalometric indices: length of soft palate (PMU; P = 0·002); mandibular plane‐hyoid bone distance (MPH; P = 0·017), maximum thickness of soft palate (Max‐SP; P = 0·018) and VT (P = 0·027). Eight patients had sleep disordered breathing (AHI ≥ 5) which was predominantly obstructive in nature (AHI = 29·4 ± 22·6). After treatment, there were significant improvements in hormonal profile: GH, mU/l (before, 51·5 ± 27·8; after, 8·0 ± 7·4; P = 0·017) and IGF‐1, nmol/l (before, 95·5 ± 23·4; after, 35·0 ± 12·4; P = 0·012); sleep‐disordered breathing: AHI (before, 29·4 ± 22·6; after, 13·4 ± 11·12; P = 0·025), snoring episodes (before, 486 ± 240; after, 165 ± 170; P = 0·05); cephalometric indices, mm: MPH (before, 18·8 ± 12·1; after, 14·8 ± 8·4; P = 0·018), VT (before, 72·3 ± 4·4; after, 69·7 ± 4·3; P = 0·05). There was a positive correlation between the reduction in GH and AHI (r = 0·738, P = 0·037).

CONCLUSIONS The findings demonstrated that there was correlation between sleep apnoea severity and soft tissue overgrowth at the upper airway region in acromegaly. They also suggest that Sandostatin® LAR® improved obstructive sleep apnoea in acromegaly, and the effect might be partly mediated via a reduction in upper airway soft tissue, in particular that of the tongue, concomitant with a reduction in GH levels.
Paradoxical elevations in serum IGF‐II and IGF binding protein‐2 in acromegaly: insights into the regulation of these peptides
Authors: Renehan Andrew G. , Toogood Andrew A. , Ryder W. David , Jones Jenny , Potten Christopher S. , O'Dwyer Sarah T. , Shalet Stephen M.
Published: March 2003

OBJECTIVE Circulating insulin‐like growth factor (IGF)‐II and IGF binding protein‐2 (IGFBP‐2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their normal regulation. This study compared serum IGF‐II and IGFBP‐2 distributions between acromegalics and a large normal adult population to explore possible determinants.

PATIENTS Sixty acromegalic patients undergoing screening colonoscopy (age range 25–81 years); normative data from 306 healthy adults (age range 20–89 years).

MEASUREMENTS Serum IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3 were measured in healthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t‐tests (unadjusted) and multiple regression models (adjusted for age and gender). Correlations were expressed as Pearson's coefficient (r).

RESULTS For acromegalic patients, GH was significantly correlated with IGF‐I (r = 0·50; P < 0·001) and IGFBP‐3 (r = 0·29; P = 0·03) but not IGF‐II or IGFBP‐2. Contrary to expectations, mean IGF‐II and IGFBP‐2 levels were significantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) µg/l and 305 (200, 410) µg/l, respectively]. Ten acromegalic patients had colorectal neoplasia but their presence did not contribute to the elevations in serum IGF‐II and IGFBP‐2. The (IGF‐I + IGF‐II)/IGFBP‐3 molar ratios were remarkably constant in both healthy adults and acromegalics, but the relationships of the ligands individually with IGFBP‐3 were not linear: as IGFBP‐3 increased, IGF‐I also increased whereas IGF‐II initially increased but then decreased. IGFBP‐2 did not correlate with IGF‐II, but molar concentration significantly correlated with the IGF‐II/IGFBP‐3 molar ratio (r = 0·40; P = 0·001).

CONCLUSIONS Serum IGF‐II and IGFBP‐2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IGF‐I + IGF‐II)/IGFBP‐3 molar ratio appears to be pivotal in determining IGF‐II values, which, in turn, expressed as a ratio of IGFBP‐3, is related to IGFBP‐2. These observations offer new insights into the regulation of these peptides.
Demonstration of anti‐TSH antibody in TSH binding inhibitory immunoglobulin‐positive sera of patients with Graves’ disease
Authors: Ochi Yukio , Hamazu Masanari , Kajita Yoshihiro , Nagata Atsuo
Published: March 2003

objectives The presence of anti‐TSH antibodies in Graves’ patients with unusually low TSH binding inhibitory immunoglobulin (TBII) has been reported. Recently, we found the first case of an anti‐TSH antibody in TBII‐positive sera of patients with Graves’ disease. The prevalence and immunological specificity of this anti‐TSH antibody were examined.

design The presence of 125I‐bovine(b) TSH binding antibody in TBII positive serum was examined by prolonged incubation of more than 1 day because only weak binding occurred after 1 h incubation at 37°C. The clinical course of these patients and binding characteristics of anti‐bTSH antibody were examined.

results The corrected method‐TBII activity (%)[1 – (a – b)/(c – d)] × 100 and the standard method‐TBII activity (%) [1 – (a – d)/(c – d)] × 100 [a, 125I‐bTSH binding with TSH receptor (R) in the presence of test serum; b, 125I‐bTSH binding with test serum; c, 125I‐bTSH binding with TSH R in the presence of normal serum; d, 125I‐bTSH binding with normal serum] were calculated. The corrected method‐TBII activity was always higher than the standard method‐TBII activity in anti‐bTSH antibody‐positive serum. Anti‐bTSH antibody‐positive cases in TBII‐positive Graves’ disease were found in approximately 1% of Graves’ patients. Anti‐bTSH antibodies were confirmed as IgG from the increase of precipitated radioactivity by adding rabbit antihuman IgG antibody after the incubation of 125I‐bTSH with test serum. These antibodies bind with not only bTSH, bTSH(α) and bLH, but also porcine (p)TSH, pTSH(α) and pFSH. However, these antibodies did not bind with human TSH. Binding of 125I‐bTSH with patient’s serum was neither inhibited by other Graves’ thyroid stimulating antibody (TSAb), nor thyroid blocking antibody (TBAb) in primary hypothyroidism.

conclusions The presence of anti‐bTSH antibody in TBII‐positive serum of high titre means that TBII‐positive sera cannot rule out the absence of anti‐bTSH. Thus, determination of 125I‐bTSH binding with test serum in TSH receptor assays is necessary to determine the precise TBII activity and to detect anti‐bTSH antibody.
Skin fibroblasts of children with idiopathic short stature show an increased mitogenic response to IGF‐I and secrete more IGFBP‐3
Authors: Kamp G. A. , Ouwens D. M. , Hoogerbrugge C. M. , Zwinderman A. H. , Maassen J. A. , Wit J. M.
Published: March 2003

objective and patients To study differences in cellular parameters of GH and IGF‐I responsiveness in skin fibroblasts of 14 children with idiopathic short stature (ISS) treated with recombinant human GH and 13 children with normal height. Secondly, to investigate whether these cellular parameters can predict the growth response to GH treatment in children with ISS.

design and measurements The mitogenic responsiveness to GH and IGF‐I was investigated by 3H‐Thymidine incorporation. Insulin‐like growth factor binding protein‐3 (IGFBP‐3) levels in the media were measured by radioimmunoassay (RIA).

results No significant mitogenic responses were observed to various doses of GH (1000, 5000 or 50·000 ng/ml) in children with ISS or controls. ISS fibroblasts showed an increased mitogenic response to IGF‐I (10 ng/ml) compared to controls (mean ± SD 5·9 ± 2·4‐ vs. 4·2 ± 1·5‐fold stimulation, P < 0·05), and GH enhanced this effect in both groups. IGFBP‐3 secretion was increased in ISS fibroblasts when compared to controls under all conditions examined (basal, 200 and 5000 ng/ml GH, 10 ng/ml IGF‐I for 24 and 48 h). High IGFBP‐3 levels were related to low mitogenic responses to IGF‐I or to GH + IGF‐I in children with ISS (r = –0·7, P < 0·05), but not in controls. Within the ISS group, an enhanced mitogenic response to IGF‐I in vitro was related to more extreme short stature before GH treatment (r = –0·70, P < 0·05) and to a relatively impaired response to high dose GH treatment in vivo (r = –0·52, P < 0·05).

conclusion The demonstration of high IGFBP‐3 levels and enhanced mitogenic response to IGF‐I shows that ISS fibroblasts have different cellular characteristics compared to controls of normal height. It is hypothesized that in ISS an alteration of the signal transduction pathway between the GH receptor and IGFBP‐3 synthesis results in a local imbalance with high IGFBP‐3 levels and lower IGF‐I availability for the IGF‐I receptor. This may be reflected by an increased IGF‐I responsiveness in vitro which is associated with an impaired capacity to grow in vivo.
Genetic analysis of the MEN1 gene and HPRT2 locus in two Italian kindreds with familial isolated hyperparathyroidism
Authors: Cetani Filomena , Pardi Elena , Giovannetti Anna , Vignali Edda , Borsari Simona , Golia Franco , Cianferotti Luisella , Viacava Paolo , Miccoli Paolo , Gasperi Maurizio , Pinchera Aldo , Marcocci Claudio
Published: March 2003

OBJECTIVES Familial hyperparathyroidism may occur as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2A), hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome and familial isolated hyperparathyroidism (FIHP). It is unclear whether the latter is a distinct genetic entity or a variant of MEN1 or HPT‐JT, where, because of reduced penetrance, only primary hyperparathyroidism (PHPT) is present. In the present study, we describe two unrelated Italian kindreds with FIHP, in which the clinical, histopathological and genetic analyses of the MEN1 gene and HPRT2 locus at 1q21‐32 suggest that both might be a variant of MEN1 and HPT‐JT syndromes.

PATIENTS AND DESIGN We studied 16 members, aged 14–50 years, of two unrelated kindreds with FIHP. Genomic DNA was isolated from peripheral blood leucocytes in all family members, and from parathyroid tissue in those who underwent parathyroidectomy.

MEASUREMENTS Ionized calcium and PTH were measured in all family members. The nine coding exons and 16 splice junctions of the MEN1 gene from constitutional DNA were amplified by the polymerase chain reaction (PCR) and sequenced. Parathyroid glands were obtained from five subjects. Allelic deletions (loss of heterozygosity, LOH) of chromosomes 11q13 and 1q21‐q32 were assessed using PYGM and D11S449, and D1S215, D1S222, D1S428, D1S412, D1S413 and D1S477, respectively. Forward primers were conjugated with 5′ fluorescent dye. PCR products were analysed using an ABI PRISM 310 sequencer.

RESULTS Five members of family 1 and three of family 2 had PHPT. A heterozygous deletion of 1 bp of the MEN1 gene in exon 10 (1785delA) was found in affected members of family 1. No MEN1 gene mutation was found in any member of family 2. LOH at 11q13 was observed in family 1 tumours, but not in those from family 2. Studies at 1q21‐32 showed LOH in two family 2 tumours, whereas a retained heterozygosity was found in the remaining member. No LOH at 1q21‐32 was found in family 1 tumours. The pathology of family 1 showed chief cell hyperplasia with a diffuse‐nodular pattern of growth. Cut surface showed no cystic structures. Typical parathyroid adenoma was diagnosed in one member of family 2 and atypical adenoma in the remaining two. These tumours showed cystic structures.

CONCLUSIONS In conclusion, we describe two unrelated kindreds with FIHP which, on the basis of histopathological and genetic studies, could be labelled as variants of the MEN1 and HPT‐JT syndromes, respectively. Therefore, an extensive analysis of the genes involved in these diseases should be performed in families with familial isolated hyperparathyroidism to identify the subset linked to the MEN1 gene or to the HPRT2 locus.
Radio‐frequency ablation for symptom control in a patient with metastatic pancreatic insulinoma
Authors: Scott Adrian , Hinwood David , Donnelly Richard
Published: March 2003

Malignant insulinomas are very rare endocrine tumours with a variable clinical course. We describe a 51‐year‐old man who had two large insulinomas resected from the body of the pancreas and 19 years later, having again become symptomatic, was found to have hepatic metastases. Medical treatment with diazoxide and octreotide failed to control his symptoms, but repeated hepatic embolization effected both symptomatic and biochemical improvements for a further 5 years. When symptoms recurred but further embolization failed to control his symptoms the hepatic metastases were treated by outpatient percutaneous radio‐frequency ablation. He remains symptom‐free 18 months later and levels of insulin and pro‐insulin have nearly normalized. The survival, with liver metastases, for 27 years in a man with a malignant insulinoma has not been described previously. Malignant insulinoma may follow a rather indolent course and symptoms respond well to locally destructive therapies. Hepatic embolization is less traumatic than hepatic lobe resection and radio‐frequency ablation offers an alternative if vascular access to the tumour is no longer possible.
Effects of GH replacement on endothelial function and large‐artery stiffness in GH‐deficient adults: a randomized, double‐blind, placebo‐controlled study
Authors: Smith J. C. , Evans L. M. , Wilkinson I. , Goodfellow J. , Cockcroft J. R. , Scanlon M. F. , Davies J. S.
Published: March 2003

objectives Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening.

design and patients In a randomized, double‐blind, placebo‐controlled study, we investigated the effects of GH replacement on endothelial function and large‐artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19–64 years) over a 6‐month period. Thirty‐two age‐ and sex‐matched healthy controls were also studied.

measurements Endothelial function was assessed using ultrasonic wall tracking to measure flow‐mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured.

results At baseline, FMD (mean ± SD) was impaired in GH‐deficient subjects vs. controls (3·4 ± 2·3 vs. 5·7 ± 2·0%, P < 0·0001), although endothelium‐independent dilatation was similar. The augmentation index was higher in GH‐deficient subjects vs. controls (23 ± 12 vs. 14 ± 14%, P < 0·01). GH‐deficient subjects had higher LDL cholesterol (4·1 ± 0·8 vs. 3·5 ± 0·8 mmol/l, P < 0·01) and lower HDL cholesterol (1·1 ± 0·3 vs. 1·4 ± 0·4 mmol/l, P < 0·01). In GH‐deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = –0·40, P < 0·05) and between FMD and the augmentation index (r = – 0·58, P < 0·01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0·0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5·0 ± 2·6 vs. 2·8 ± 1·9%, P < 0·01). There were decreases in central aortic systolic pressure (117 ± 15 vs. 123 ± 17 mmHg, P < 0·01), diastolic pressure (82 ± 10 vs. 86 ± 8 mmHg, P < 0·01) and the augmentation index (22 ± 8%vs. 26 ± 10%, P < 0·05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3·5 ± 0·8 vs. 4·2 ± 0·8 mmol/l, P < 0·01). There were no significant changes in the placebo group.

conclusions Adult GHD is associated with endothelial dysfunction and increased large‐artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.
Increased menin expression in sporadic pituitary adenomas
Authors: Wrocklage Christian , Gold Heidrun , Hackl Wolfgang , Buchfelder Michael , Fahlbusch Rudolf , Paulus Werner
Published: March 2003

background Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour‐suppressor gene are responsible for multiple endocrine neoplasia type 1, and menin, the MEN1 gene product, is usually downregulated or truncated in MEN1‐associated adenomas. In contrast, exonic MEN1 mutations seem to be very rare in sporadic (MEN1‐unrelated) pituitary adenomas, and it has been suggested that menin does not play a major role in these tumours. However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms.

patients and measurements We screened MEN1 coding regions and flanking intronic sequences of 136 sporadic pituitary adenomas by temporal temperature gradient gel electrophoresis (TTGE) and studied menin expression by immunoblotting in 11 of these tumours.

results Sequencing of DNAs showing aberrant migration on TTGE revealed five somatic MEN1 mutations, including two missense mutations (F134L, E530K), a 2‐bp deletion in exon 10 (c.1567–1568del) leading to a premature stop codon, and two 3‐bp deletions in intron 5 (g.5236–5238del, g.5237–5239del). These mutations have not been reported previously in studies analysing the MEN1 gene. Immunoblotting showed menin upregulation in all adenomas examined (including one case with a missense mutation) from 1·7‐fold to 10·4‐fold (mean, 4·2‐fold) compared to non‐neoplastic adenohypophysis.

conclusions Our data suggest that neither MEN1 mutations nor menin downregulation play a significant role in the development of sporadic pituitary adenomas.