bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary thyroid disorders in endogenous Cushing's syndrome
Authors: Niepomniszcze H , Pitoia F , Katz SB , Chervin R , Bruno OD
Published: January 2005

OBJECTIVE: To study the prevalence of primary thyroid disorders in patients who underwent endogenous hypercortisolism. DESIGN: Retrospective evaluation of 59 patients with Cushing's syndrome (CS) who had, at least, a record of thyroid palpation by expert endocrinologists and basal measurements of TSH by second generation assays. When available, tri-iodothyronine and thyroxine serum levels, TRH-TSH tests and anti-thyroid antibodies were also analyzed. There were two age- and gender-matched control groups. The 'goiter control group' comprised 118 healthy subjects who underwent thyroid palpation. The 'antibody control group' was composed of 40 individuals who attended the blood bank of our hospital. Antibodies against thyroperoxidase and measurements of TSH were analyzed in their blood samples. METHODS: Available files of 83 CS patients admitted to our endocrine unit from 1985 to 1998 were examined. Fifty-nine patients (52 women and 7 men) with a mean age of 36.2 years (range 14-61 years) met the above requirements. Diagnosis of hypercortisolism had been established by a standard 1-mg overnight dexamethasone suppression test and urinary free cortisol (UFC). Etiological diagnosis involved dynamic testing, measurements of ACTH levels and imaging techniques. After treatment, all but one of the patients were cured or controlled of their hypercortisolism. This was established by the finding of subnormal serum cortisol concentrations and/or subnormal 24-h UFC levels. Primary thyroid disorders were defined by the presence of one or more of the following diagnostic criteria: (i) goiter, (ii) positive anti-thyroid antibodies and/or (iii) primary thyroid function abnormalities. RESULTS: Eighteen (30.5%) patients had goiter (diffuse in 78% and nodular in 22%), 14 (23.7%) had primary subclinical hypothyroidism and 5 (8.4%) had hyperthyroidism. In 41 patients evaluated for antithyroid antibodies, it was found that 23 (56.1%) had positive titers. In a group of patients in which thyroid autoantibodies were measured both before and after resolution of hypercortisolism, prevalences of positive titers were 26.7% and 86.7% respectively (P=0.001). The overall frequency of primary thyroid abnormalities in our patients with Cushing's syndrome was 55.9%. CONCLUSIONS: Patients with endogenous Cushing's syndrome exhibit a remarkably high prevalence of primary thyroid disease. Resolution of hypercortisolism seems to trigger the development of autoimmune thyroid disorders in presumably predisposed subjects.
Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism
Authors: Villablanca A , Wassif WS , Smith T , Hoog A , Vierimaa O , Kassem M , Dwight T , Forsberg L , Du Q , Learoyd D , Jones K , Stranks S , Juhlin C , Teh BT , Carling T , Robinson B , Larsson C
Published: January 2005

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is a hereditary disorder characterised by uni- or multiglandular parathyroid disease. A subset of families are likely to be genetic variants of other familial tumour syndromes in which PHPT is the main feature, for example multiple endocrine neoplasia type 1 (MEN 1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT). OBJECTIVE: To investigate seven families diagnosed with FIHP, each with two to eight affected family members, to clarify the underlying genetic mechanism. METHODS: The entire MEN1 gene was sequenced for germline mutations and, in addition, tumour specimens were analysed in comparative genomic hybridisation and loss of heterozygosity studies. RESULTS: Two families exhibited MEN1 mutations, L112V and 1658delG, which were associated with loss of the wild-type 11q13 alleles in all tumours analysed. In the remaining five families, no MEN1 mutation was identified. CONCLUSION: These results support the involvement of the MEN1 tumour suppressor gene in the pathogenesis of some of the FIHP kindreds. However, loss on chromosome 11 was seen in all tumours exhibiting somatic deletions, although in two families the tumour deletions involved 11q distal to MEN1. We conclude that the altered MEN1 gene function is of importance in the development of FIHP.
An improved computational method to assess pituitary responsiveness to secretagogue stimuli
Authors: Sartorio A , De Nicolao G , Liberati D
Published: January 2005

OBJECTIVE: The quantitative assessment of gland responsiveness to exogenous stimuli is typically carried out using the peak value of the hormone concentrations in plasma, the area under its curve (AUC), or through deconvolution analysis. However, none of these methods is satisfactory, due to either sensitivity to measurement errors or various sources of bias. The objective was to introduce and validate an easy-to-compute responsiveness index, robust in the face of measurement errors and interindividual variability of kinetics parameters. DESIGN: The new method has been tested on responsiveness tests for the six pituitary hormones (using GH-releasing hormone, thyrotrophin-releasing hormone, gonadotrophin-releasing hormone and corticotrophin-releasing hormone as secretagogues), for a total of 174 tests. Hormone concentrations were assayed in six to eight samples between -30 min and 120 min from the stimulus. METHODS: An easy-to-compute direct formula has been worked out to assess the 'stimulated AUC', that is the part of the AUC of the response curve depending on the stimulus, as opposed to pre- and post-stimulus spontaneous secretion. The weights of the formula have been reported for the six pituitary hormones and some popular sampling protocols. RESULTS AND CONCLUSIONS: The new index is less sensitive to measurement error than the peak value. Moreover, it provides results that cannot be obtained from a simple scaling of either the peak value or the standard AUC. Future studies are needed to show whether the reduced sensitivity to measurement error and the proportionality to the amount of released hormone render the stimulated AUC indeed a valid alternative to the peak value for the diagnosis of the different pathophysiological states, such as, for instance, GH deficits.
Reduced microvascular perfusion and reactivity in adult GH deficient patients is restored by GH replacement
Authors: Hana V , Prazny M , Marek J , Skrha J , Justova V
Published: January 2005

BACKGROUND: An increased cardiovascular risk and mortality in hypopituitary patients receiving conventional hormonal treatment without GH replacement have been shown in several studies. Various atherogenic risk factors including endothelial dysfunction - an early event in the atherogenesis - are more expressed in adults with GH-deficiency (GHD). Changes in microcirculation and vascular reactivity could represent an early marker of developing vascular changes. OBJECTIVE: To evaluate the microcirculation and vascular reactivity in a GHD state before and during GH replacement. SUBJECTS, METHODS AND DESIGN: Thirteen adult patients (ten men, mean age 40+/-9 years) with severe GHD were studied. The skin microvascular perfusion and reactivity were measured by laser-Doppler flowmetry on the forearm. Two dynamic tests for vascular perfusion and reactivity were used - postocclusive reactive hyperemia (PORH) and thermal hyperemia (TH) at 44 degrees C. Measurements were performed before and after 6 and 12 months on GH replacement with a dose of GH that normalized IGF-I serum levels. The parameters of tissue perfusion and vascular reactivity measured in GHD were compared with values during GH treatment and with the results of the control group. RESULTS: Peak flow during TH in GHD patients was significantly reduced before GH treatment when compared with healthy subjects (means+/-s.e.m., 68+/-6.6 vs 111+/-8.3 perfusion units (PU), P<0.001) and normalized on GH treatment (109+/-12.7 PU). The velocity of perfusion increase during TH before treatment was significantly reduced in GHD as well (0.84+/-0.07 vs 1.53+/-0.19 PU/s, P<0.03) and normalized on GH treatment (1.38+/-0.24 PU/s). The PORH was also significantly reduced in GHD compared with controls (PORH(max) 414+/-63 vs 528+/-58%, P<0.05) and during GH treatment was restored to values not different from controls (642+/-86%, P=NS). CONCLUSIONS: Skin microcirculation and vascular reactivity measured by laser-Doppler flowmetry is significantly reduced in GHD adults and is restored during GH replacement therapy. Reduced tissue perfusion and reactivity probably reflect the endothelial dysfunction in the GHD state. Reduced nitric oxide production and bioavailability and also other factors like increased sympathetic activity and reduced conversion of thyroxine to triiodothyronine in the GHD state can contribute to changes in microcirculation. Restoration of vascular reactivity by GH replacement might have favorable clinical consequences on the increased vascular morbidity of GHD patients. Reduced skin microvascular perfusion and reactivity in GHD probably contribute to the impaired thermoregulation - a clinical symptom of GHD.
Effect of low-dose of recombinant human growth hormone on bone metabolism in elderly women with osteoporosis
Authors: Sugimoto T , Kaji H , Nakaoka D , Yamauchi M , Yano S , Sugishita T , Baylink DJ , Mohan S , Chihara K
Published: January 2005

BACKGROUND: There has been increasing evidence that the growth hormone (GH)-IGF-I axis plays an important part in the maintenance of bone mass. However, controversy still exists as to the effect of GH treatment on bone mineral density (BMD) in elderly patients with osteoporosis. OBJECTIVE: To investigate the effect of low-dose GH treatment on markers of body composition and bone turnover, serum concentrations of IGF-I and IGF-binding proteins (IGFBPs), and BMD at the radius and lumbar spine in eight elderly Japanese women with osteoporosis. METHODS: Participants were treated with GH as a single daily subcutaneous injection (0.125 IU/kg per week; 0.00595 mg/kg per day) for 48 weeks. RESULTS: Markers of bone formation and bone resorption were both increased up to 24 weeks of GH treatment. The bone formation markers remained increased during GH treatment, whereas the bone resorption markers returned to baseline values after 24 weeks of GH treatment. GH treatment caused a rapid (within 2 weeks) and sustained increase in serum IGF-I concentration. As for IGFBPs, serum concentrations of IGFBPs-2, -3 and -4 did not change significantly during GH treatment. In contrast, GH treatment caused a gradual increase in serum IGFBP-5 concentration, with a significant increase seen 48 weeks after the start of GH treatment. Radial BMD seemed to be increased during the late period of GH treatment, although the change was not significant. Lumbar BMD did not change during GH treatment. GH treatment caused a significant increase in hand grip strength. None of the GH-treated participants had new fractures and side effects such as edema and joint pain. Radial BMD was significantly increased after discontinuation of GH treatment for another 48 weeks and a similar tendency was observed at the lumbar spine (7.1+/-2.3% above pretreatment values for the radius and 3.6+/-2.0% for the lumbar spine). CONCLUSIONS: Low-dose GH treatment attenuated the decrease in muscle strength and bone mass in elderly women without side effects, although changes in nutrition and exercise might affect BMD. The present findings provide useful information regarding the use of low-dose GH treatment in elderly women with osteoporosis.
Hormonal evaluation and mutation screening for steroid 21-hydroxylase deficiency in patients with unilateral and bilateral adrenal incidentalomas
Authors: Patocs A , Toth M , Barta C , Sasvari-Szekely M , Varga I , Szucs N , Jakab C , Glaz E , Racz K
Published: January 2005

OBJECTIVE: The aims of the present study were (a) to examine the occurrence of 21-hydroxylase gene (CYP21) mutations in patients with unilateral and bilateral adrenal incidentalomas and (b) to correlate the results of mutation screening with hormonal parameters of 21-hydroxylase deficiency. DESIGN: The frequency of the eight commonly occurring CYP21 mutations in blood DNA samples of 19 patients with bilateral, as well as in blood and tumoral tissue DNA samples of 31 patients with unilateral adrenal incidentalomas, was determined. In all patients, hormonal evaluation for 21-hydroxylase deficiency was performed using measurements of basal and ACTH-stimulated plasma 17-hydroxyprogesterone (17-OHP) concentrations. METHODS: Blood and tumoral DNA samples were analyzed by allele-specific PCR for the detection of the eight commonly occurring CYP21 mutations (deletion/large gene conversion, intron 2 splicing, Ile172Asn, exon 6 cluster, Val281Leu, Leu307insT, Gln318Stop and Arg356Trp mutations). Plasma 17-OHP concentrations were measured by radioimmunoassay. RESULTS: Of the 19 patients with bilateral adrenal incidentalomas, one patient had homozygous (Val281Leu) and three patients had heterozygous germline CYP21 mutations (Val281Leu in two cases and Arg356Trp in one case). Heterozygous germline CYP21 mutations were also detected in five of the 31 patients with unilateral adrenal incidentalomas (Ile172Asn in three cases and Val281Leu in two cases). Mutation screening of tumoral DNA in unilateral incidentalomas showed the presence of corresponding germline mutations but no additional somatic mutations were found. ACTH-stimulated plasma 17-OHP concentrations were above 1500 ng/dl in all patients with bilateral incidentalomas who had homozygous and heterozygous CYP21 mutations, but heterozygous carriers with unilateral incidentalomas had highly variable ACTH-stimulated plasma 17-OHP levels (between 111 and 1705 ng/dl). CONCLUSIONS: These results suggest a similar frequency of germline CYP21 mutations in patients with bilateral and unilateral adrenal incidentalomas (21.1% and 16.1% respectively). Therefore, it cannot be ruled out that, in at least some patients, CYP21 mutations may play a role in the pathomechanism of bilateral and unilateral adrenal incidentalomas. However, the lack of clear association of CYP21 mutations with increased ACTH-stimulated plasma l7-OHP response, especially in patients with unilateral incidentalomas, suggests that the effect of CYP21 mutations on adrenocortical tumor formation may also involve mechanism(s) independent of ACTH-induced changes in 17-OHP secretion.
Thyrotropin-releasing hormone regulates the diurnal variation of pyroglutamyl aminopeptidase II activity in the male rat adenohypophysis
Authors: Angel Vargas M , Uribe RM , Cisneros M , Romero F , Gonzalez S , Joseph-Bravo P , Charli JL
Published: January 2005

OBJECTIVE: Thyrotropin-releasing hormone (TRH) is inactivated in the extracellular compartment by pyroglutamyl aminopeptidase II (PPII), a narrow specificity ectopeptidase present in the brain and in the lactotrophs of the adenohypophysis. TRH and various hypothalamic/paracrine agents regulate the activity of PPII on the surface of adenohypophyseal cells in primary culture. The activity of the hypothalamic-pituitary-thyroid axis presents circadian variations including an increase of serum thyrotropin levels in the early hours of the day. The purpose of this study was to determine whether adenohypophyseal PPII activity fluctuates during the daytime in the male rat and the role of TRH in these regulatory events in vivo. RESULTS: Adenohypophyseal PPII specific activity and mRNA levels presented diurnal variations. A decrease in specific activity occurred with a minimum between 0930 and 1130 h, associated with increased serum thyrotropin levels. PPII mRNA levels were lowest at 0800 h. Intraperitoneal injection at 0800 or 1000 h of [3-Me-His(2)]-TRH, a potent agonist of the TRH receptor, reduced PPII specific activity at 30 min post-injection which was followed by a return to basal levels at 2 h. A second phase of decrease occurred between 4 and 8 h post-injection. Intravenous injection of a TRH-immune serum induced, at 2 h post-injection, an increase in adenohypophyseal PPII specific activity, which lasted up to 6 h. CONCLUSIONS: Adenohypophyseal PPII activity and mRNA levels fluctuate during the day; TRH down-regulates PPII activity in vivo, contributing to some of these variations. These new findings, and previous data, suggest that adenohypophyseal PPII activity varies in distinct physiological events, in response to endocrine and hypothalamic/paracrine factors, potentially modulating responses to TRH.
Development of an experimental ovarian tumor: immunocytochemical analysis
Authors: Sorianello E , Fritz S , Beyer C , Hales DB , Mayerhofer A , Libertun C , Lux-Lantos V
Published: January 2005

OBJECTIVE: The aim of the present work was to study whether immunocytochemical parameters present in the normal ovary were altered after tumor development under high gonadotropin levels. METHODS: Ovarian tumors (luteoma): castrated female rats had an ovary grafted into the spleen; tumors were left to develop for 1, 2, 3 or 7 months. The presence of apoptotic cells (TUNEL method) and the expression of proliferating cell nuclear antigen (PCNA), gap junction protein (Cx43), steroidogenic acute regulatory protein (StAR), aromatase and synaptosome-associated protein of 25 kDa (SNAP-25) were determined by immunocytochemistry. Some of these findings were confirmed by RT-PCR (Cx43, StAR, SNAP-25). Inhibin subunit mRNAs were investigated by Northern blot. RESULTS: PCNA staining of tumors was mainly found in granulosa cells of transforming follicles and was absent from luteinized follicles. A nearly complete absence of apoptosis was observed. Cx43 was mainly found in follicles, while it was very weakly expressed or absent in luteinized follicles. StAR protein expression, indicating active steroidogenesis, was demonstrated only in luteinized follicles and in thecal cells, but was absent from granulosa cells. Aromatase immunoreactivity was very intense in granulosa and also present in luteal cells. Membrane-associated and cytoplasmic SNAP-25 immunostaining was determined in patches of endocrine cells in the follicles, as well as in the luteinized follicles. The expression of mRNAs for Cx43, StAR and SNAP-25 (RT-PCR) and inhibin subunits (Northern blots) were confirmed in 1-, 3- and 7-month-old tumors. CONCLUSIONS: These results indicated that luteoma most likely develop from unruptured follicles by hypertrophy and proliferation of follicular cells. Circulating gonadotropins seem to play a fundamental role in maintaining the expression of proteins typically expressed in normal ovary, while avoiding apoptosis in this tissue.
Developmental expression and spermatogenic stage specificity of transcription factors GATA-1 and GATA-4 and their cofactors FOG-1 and FOG-2 in the mouse testis
Authors: Ketola I , Anttonen M , Vaskivuo T , Tapanainen JS , Toppari J , Heikinheimo M
Published: January 2005

OBJECTIVE: The transcription factors GATA-1 and GATA-4 have been implicated in the regulation of testicular development and function. Their cofactors FOG-1 and FOG-2 are expressed in the gonads, but their cell-specific and developmental expression in the testis remains unresolved. Therefore, we analyzed GATA-1, GATA-4, FOG-1 and FOG-2 expression in detail, from undifferentiated male urogenital ridge to adult testis. METHODS: Immunohistochemistry and in situ hybridization were applied on mouse testicular samples. RESULTS: GATA-4 and FOG-2, but not GATA-1 or FOG-1, were expressed as early as in the male urogenital ridge. FOG-2 expression was localized in the Sertoli cells at embryonal day 12.5 (E12.5), but it diminished with advancing fetal testicular development. In E17.5 testis, FOG-2 was present only in the testicular capsule and a subset of fetal Leydig cells. FOG-1 was expressed from E15.5 Sertoli cells onwards, whereas GATA-1 was not detected during the fetal period at all. In the postnatal testis, FOG-2 was abundantly expressed immediately after birth, but in adult testis its expression was predominantly restricted to stage VII-XII seminiferous tubules. Stage specificity was also found for FOG-1, which, similarly to GATA-1, was abundantly expressed in stage VII-XII tubules during adulthood. CONCLUSIONS: Our results indicate that FOG-2, in addition to GATA-4, has a role in early gonadal development and sexual differentiation, and FOG-1 at later fetal stages, while GATA-1 executes its action postnatally. The findings suggest that, in contrast to the hematopoietic system and the heart, GATA-1 and GATA-4 do not use FOG-1 and FOG-2 respectively as their only cofactors during the early stages of testicular development.
Nerve growth factor induces the re-expression of functional androgen receptors and p75(NGFR) in the androgen-insensitive prostate cancer cell line DU145
Authors: Sigala S , Tognazzi N , Rizzetti MC , Faraoni I , Missale C , Bonmassar E , Spano P
Published: January 2005

BACKGROUND: One of the paracrine/autocrine factors regulating prostate growth and differentiation is nerve growth factor (NGF). The role of NGF and its receptors in the prostate, however, remains controversial. We have shown that NGF treatment of human prostate cancer cell lines reduced their tumorigenicity, both in vitro and in vivo. OBJECTIVE: To investigate the involvement of NGF as a differentiation factor in prostate cancer cells. DESIGN: We exposed the androgen-independent/androgen receptor (AR)-negative prostate cancer cell line DU145 to NGF to study whether this neurotrophin could revert DU145 cells to a less malignant phenotype. METHODS: DU145 cells were treated with NGF, then ARs and NGF receptor p75(NGFR) expression and telomerase activity were studied. Finally, we investigated whether re-expression of ARs could restore the androgen sensitivity in this cell line. RESULTS AND CONCLUSIONS: NGF treatment induced a reversion of DU145 cells to a less malignant phenotype, characterized by the re-expression of ARs and p75(NGFR) NGF receptors. Re-expression of ARs restored the androgen sensitivity, as suggested by the fact that exposure to dihydrotestosterone stimulated the growth of NGF-treated DU145 cells. This effect was blocked by androgen antagonist drugs, such as hydroxyflutamide and cyproterone acetate, which also induced apoptotic death of NGF-treated cells. The hypothesis that a differentiation pathway is activated by exogenous NGF in DU145 cells is also supported by findings indicating that NGF-treated DU145 cells expressed a low telomerase activity, as a result of a decrease in human telomerase reverse transcriptase transcription.
Insights into obesity and insulin resistance from the study of extreme human phenotypes
Authors: O'Rahilly S
Published: January 2005

The detailed study of rare, extreme human phenotypes has a long and distinguished history in endocrinology. Such individuals have often acted as 'experiments of nature' providing important novel information regarding endocrine physiology and mechanistic insights relevant to the study of more common endocrine disorders. This review presents a personal experience of the study of two such extreme phenotypes, obesity and severe insulin resistance.
Thyroid dysfunction during pregnancy and in the first postpartum year in women with diabetes mellitus type 1
Authors: Gallas PR , Stolk RP , Bakker K , Endert E , Wiersinga WM
Published: January 2005

BACKGROUND: The prevalence of thyroid dysfunction in pregnancy and in the first postpartum year (postpartum thyroid dysfunction (PPTD)) in women with diabetes mellitus type 1 (DM1) is known to be higher than in the general population. To assess prevalence, incidence and risk factors in The Netherlands we performed a prospective cohort study. DESIGN: From 1994 to 1998, 126 women with DM1 from eight Dutch clinics were included. TSH, free thyroxine, free tri-iodothyronine and anti-thyroid peroxidase antibodies (TPO-ab) were measured pre-pregnancy, in the first and last trimester of pregnancy and at 1.5, 3, 6, 9 and 12 months after delivery. RESULTS: Eighty-two women completed the study. Thyroid dysfunction during pregnancy was observed in 22.5% (first trimester) and 18.4% (third trimester), and mostly consisted of subclinical hypothyroidism. Baseline characteristics of women with thyroid dysfunction in pregnancy did not differ from those without thyroid dysfunction. Overt PPTD was seen in 15.9%. Incidence of PPTD was 10%. Patients with PPTD were slightly older than those without PPTD and the prevalence of TPO-ab was higher in these women. CONCLUSION: In women with DM1 the prevalence of thyroid dysfunction during pregnancy and overt PPTD is 3-fold higher than in the general Dutch population. Risk factors are age and TPO-ab. Given the possible impact on psychomotor development of the offspring and on well-being of the mother these data suggest there is a case for screening (pre-)pregnant women with DM1 for TSH and TPO-ab.
Increased intima-media thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with primary hyperparathyroidism
Authors: Nuzzo V , Tauchmanova L , Fonderico F , Trotta R , Fittipaldi MR , Fontana D , Rossi R , Lombardi G , Trimarco B , Lupoli G
Published: January 2005

OBJECTIVE: Despite the increasing evidence that primary hyperparathyroidism (PHPT) contributes to greater risk of cardiovascular morbidity and mortality, its exact role in the development of cardiovascular changes and its clinical significance are still controversial. Given the multiple influence of PHPT on the cardiovascular system, this study aimed to assess the effects of PHPT on blood pressure profile, and on features of the heart and arterial vessels in normotensive symptomless patients. DESIGN: Twenty patients (8 males and 12 females) with a median age of 51.5 years (range 44 to 65 years) were evaluated and the results were compared with those of 20 controls matched for age, gender and body mass index. Patients' parathyroid hormone levels ranged from 172 to 454 pg/ml and Ca levels ranged from 11.4 to 13.5 mg/dl. Fasting levels of glucose, insulin, total and high density lipoprotein cholesterol and triglycerides were within the normal range in all subjects recruited. METHODS: Twenty-four-hour blood pressure profile, left ventricle (LV) dimension and carotid artery anatomy were investigated, the latter two by ultrasonography. RESULTS: No difference was found between the patients and controls in blood pressure profile, when the following parameters were considered: supine systolic/diastolic pressure, average 24-h systolic, diastolic and mean arterial pressure, day-time mean arterial pressure and fall in nocturnal blood pressure (-17% and -18% respectively). Heart rate and all parameters of LV mass were similar in patients and controls. The only alteration found in patients was in significantly greater carotid intimal-medial thickness (IMT) (P<0.001). Atherosclerotic plaques were more frequent in patients than in controls, with a difference reaching a trend (40% vs 10%, chi(2)=4.8; P=0.091). Considering that the carotid IMT is considered to be a marker of systemic atherosclerosis, our finding suggests early atherosclerotic changes in PHPT. No correlation was found between the severity and cardiovascular manifestation of PHPT. CONCLUSIONS: Vascular changes may occur due to a combination of structural and functional impairments in PHPT patients, likely as a result of altered calcium metabolism and impaired equilibrium of other factors regulating vascular function. Both extent and duration of PHPT can play a relative role in the development of cardiovascular complications. Considering that PHPT is now recognized as a quite common and often symptomless endocrine disorder, the evidence of cardiovascular manifestation in normotensive patients, found by this morphological study, suggests a possible implication for the management of such patients. In this light, screening for abnormalities in cardiovascular system function should be recommended in all PHPT subjects.
A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome
Authors: Colak R , Kelestimur F , Unluhizarci K , Bayram F , Sahin Y , Tutus A
Published: January 2005

OBJECTIVE: Numerous studies have found elevated androgen production by the adrenal glands in patients with polycystic ovary syndrome (PCOS). However, the role and the mechanisms responsible for the adrenal androgen excess in women with PCOS are not well understood. DESIGN: Our aim was to compare 17-hydroxyprogesterone (17-OHP), androstenedione, dehydroepiandrosterone sulfate (DHEAS) and cortisol responses to a low dose (1 microg) ACTH stimulation test (LDT) with the responses to a standard dose (250 microg) ACTH stimulation test (SDT) in patients with PCOS. METHODS: Fifty women with PCOS (mean age 25.4+/-0.7 years) and 20 healthy women (mean age 27.3+/-2.2 years) were included in the study. The patients and controls underwent ACTH stimulation tests with 1 microg and 250 microg synthetic ACTH in the follicular phase of their cycles. Venous blood was drawn at 0, 30 and 60 min for determination of serum cortisol, 17-OHP, androstenedione and DHEAS levels. RESULTS: In PCOS subjects, peak and area under the curve (AUC) 17-OHP (9.3+/-0.3 nmol/l, 378.4+/-61 nmol/lx60 min), androstenedione (15.6+/-0.6 nmol/l, 806.4+/-52 nmol/lx60 min) and DHEAS (7.5+/-0.4 micromol/l, 385.6+/-25.5 micromol/lx60 min) responses to SDT were significantly higher than the levels in healthy women (respectively 5.7+/-0.3 nmol/l and 249.4+/-52.2 nmol/lx60 min for 17-OHP; 9.1+/-0.3 nmol/l and 413.7+/-31.6 nmol/lx60 min for androstenedione; 4.3+/-0.4 micromol/l and 224.9+/-24.5 micromol/lx60 min for DHEAS) (P<0.05). Peak and AUC cortisol responses to SDT were similar in PCOS and control subjects. Peak and AUC cortisol and 17-OHP responses to LDT in women with PCOS were similar to the values obtained in healthy women. Peak androstenedione (12.5+/-0.6 nmol/l) and peak (6.5+/-0.5 nmol/l) and AUC (336.3+/-22.4 micromol/lx60 min) DHEAS responses to LDT were significantly higher in women with PCOS. CONCLUSIONS: These results show that LDT is capable of revealing the adrenal hyperactivity in women with PCOS. Adrenal P450c17alpha enzyme dysregulation in PCOS is revealed by ACTH stimulation at a pharmacological dose (250 microg) but not by a physiological dose (1 microg). LDT is able to demonstrate adrenal hyperactivity characterized by an increase in DHEAS levels.
Molecular defects of the CYP21 gene in Spanish girls with isolated precocious pubarche
Authors: Potau N , Rique S , Eduardo I , Marcos V , Ibanez L
Published: January 2005

OBJECTIVE: To determine the frequency of mutant alleles in the CYP21 gene in Spanish girls presenting with precocious pubarche (PP) and to assess the relationships between genotype and endocrine-metabolic variables. DESIGN: Fifty-three unrelated girls with a history of PP (14 prepubertal, 8 pubertal and 31 postmenarcheal) and 35 controls were studied. METHODS: Genomic DNA was extracted from peripheral blood leukocytes. After selection against the pseudogen, an allele-specific PCR was used to identify 14 known mutations in the CYP21 gene. The mutations studied were Pro30Leu, splice intron 2, Ilel72Asn, Cluster E(6), Glyl92Ser, Ins T, GT-CT, Gln318-stop, Arg357Trp, Trp406-stop, Pro453Ser, Arg483Pro, Arg483 frameshift and Val281Leu. A standard 2-h oral glucose tolerance test was performed in all PP girls. Ovarian 17-hydroxyprogesterone (17-OHP) responses to gonadotrophin-releasing hormone-agonist stimulation was assessed in postmenarcheal PP girls. RESULTS: Thirteen PP girls and eight control girls were heterozygous for one of the mutations studied. The frequency of the carrier status was 25% and 23% in the PP and control groups respectively. Severe mutations were found in 33% of the carrier girls. Serum 17-OHP responses to ACTH stimulation were similar in carriers and non-carriers (351+/-65 vs 334+/-22 ng/dl). The presence of ovarian hyperandrogenism and/or hyperinsulinism was also not related to the carrier status. CONCLUSION: The incidence of molecular defects in the CYP21 gene in the present study was comparable in the PP and control groups. We found no relationship between the presence of carrier status and endocrine-metabolic abnormalities. Prospective studies of larger cohorts of PP girls are needed to ascertain the long-term clinical relevance of CYP21 heterozygosity.
Long-term follow-up study of patients with adrenal incidentalomas
Authors: Libe R , Dall'Asta C , Barbetta L , Baccarelli A , Beck-Peccoz P , Ambrosi B
Published: January 2005

BACKGROUND: The incidence of adrenal incidentalomas has sharply increased in recent decades and concurrent subtle endocrine abnormalities, or even subclinical conditions, have been identified. Nonetheless, data concerning possible changes in adrenal size and/or hormonal pattern during follow-up are still inadequate. OBJECTIVE: To evaluate long-term morphological and functional evolution of adrenal incidentalomas after initial diagnosis and to identify possible risk factors for hormonal hyperactivity and mass enlargement. PATIENTS: Sixty-four patients (34-79 years) were followed-up for 12-120 months (median 25.5 months). Initial computerized tomography scan showed a unilateral mass in 51 patients and bilateral lesions in 13 patients. Average mass diameter at diagnosis was 2.5+/-0.1 cm (range 1.0-4.0). Twelve patients had subclinical Cushing's syndrome, 41 had mild hormonal alterations, and 11 had normal adrenal function at baseline. All patients were investigated by morphological and functional evaluation 6 and 12 months after diagnosis, and then at 1-year intervals. RESULTS: During follow-up, a mass size increase >/=1 cm was observed in 13 patients, and 18 developed further subtle endocrine alterations. Cumulative risk of developing endocrine abnormalities was 17% at 1 year, 29% at 2 years, and 47% at 5 years. The risk was higher in the first 2 years of follow-up if the initial tumor diameter was >or=3 cm. Overall, cumulative risk of mass enlargement was 6% at 1 year, 14% at 2 years, and 29% at 5 years, and it was greater in patients with normal adrenal function than in those with subtle hormonal abnormalities (P<0.05). One female subject showed a mass enlargement after 6 months of follow-up and was eventually diagnosed with non-Hodgkin's lymphoma. CONCLUSIONS: Patients with an adrenal incidentaloma are at risk for tumor growth and development of hormonal alterations. The risk of adrenal malignancy, although not elevated, also indicates the need for long-term follow-up.
Apolipoprotein E gene determines serum testosterone and dehydroepiandrosterone levels in postmenopausal women
Authors: Zofkova I , Zajickova K , Hill M , Horinek A
Published: January 2005

OBJECTIVE: Apolipoprotein E (ApoE) is believed to play an important role in lipid metabolism and has been found to be related to diseases associated with ageing, the important characteristic of which is decline in circulating sex steroids, including androgen. DESIGN: To find the relationships of levels of serum testosterone and its precursor, dehydroepiandrosterone (DHEA), to ApoE polymorphism in 113 postmenopausal Caucasian women. METHODS: The ApoE genotype was assessed by polymerase chain reaction and CfoI endonuclease digestion. ApoE genotype distribution was as follows: E2/3, 15%; E3/3, 71.7%; E2/4, 1.8%; E3/4, 10.6; and E4/4, 0.89%. The differences in serum androgen levels between genotypes were evaluated by ANCOVA and least significant difference (LSD) multiple comparisons test after adjustment for body mass index, age and/or years since menopause. RESULTS: Significant intergroup differences between the most frequent allele combination (2/3, 3/3 and 3/4) in serum DHEA levels were found (P<0.05, ANCOVA). DHEA levels were higher in women with the E3/4 allele combination than in the E3/3 genotype (P<0.01, LSD multiple comparisons). In serum testosterone levels, borderline intergroup differences were found (P<0.07, ANCOVA). Higher testosterone levels were found in the E3/4 allele combination as compared with E3/3 (P<0.05, LSD multiple comparisons). Dose effect of E4 allele analysis indicated higher serum DHEA and testosterone levels in women with the E4 allele present than in women with the E4 allele absent (P<0.003 for DHEA, P<0.007 for testosterone, ANCOVA). CONCLUSIONS: Circulating testosterone and DHEA are associated with the ApoE genotype, which may render women carrying the allele E4 more susceptible to the development of some diseases associated with ageing and menopause [corrected].
Chromosome 22q in pancreatic endocrine tumors: identification of a homozygous deletion and potential prognostic associations of allelic deletions
Authors: Wild A , Langer P , Celik I , Chaloupka B , Bartsch DK
Published: January 2005

OBJECTIVE: A variety of human tumors frequently show allelic deletions of chromosome 22q, suggesting that inactivation of one or more tumor suppressor genes in this region is important for their tumorigenesis. METHODS: In this study, 23 patients with pancreatic endocrine tumors (PETs), including gastrinomas, VIPomas and non-functioning islet cell carcinomas, were analyzed for loss of heterozygosity (LOH) on chromosome 22q with 12 microsatellite and 7 sequence tagged site markers. RESULTS: LOH on chromosome 22q was identified in 22 of 23 (96%) PETs. Markers in the chromosomal region 22q12.1 revealed LOH rates up to 85%. Notably, one tumor revealed a homozygous deletion in a second region at 22q12.3. LOH at this locus occurred more frequently in tumors with distant metastases (10 of 11) compared with tumors without distant metastases (3 of 12; P=0.0057) and, overall, allelic loss of 22q is positively correlated with distant metastases (r=0.78; P<0.0001). CONCLUSIONS: These findings are suggestive for novel tumor suppressor gene loci at chromosome 22q that might contribute to the pathogenesis of PETs, especially to the development of distant metastases.
Role of galectin-3 immunodetection in the cytological diagnosis of thyroid cystic papillary carcinoma
Authors: Papotti M , Volante M , Saggiorato E , Deandreis D , Veltri A , Orlandi F
Published: January 2005

OBJECTIVE: Cystic thyroid lesions can harbour an occult papillary carcinoma, which fine needle aspiration (FNA) biopsy may fail to detect. Recently, new markers such as galectin-3 lectin have been proposed to distinguish benign from malignant thyroid lesions of follicular origin. The aim of this study was to assess the role of galectin-3 immunodetection in a series of FNA cytological samples of benign and malignant thyroid cystic nodules. METHODS: We retrospectively analysed galectin-3 expression by immunoperoxidase staining on 32 cytological paraffin-embedded samples of cystic papillary carcinoma and on 12 samples of benign cysts, both obtained by FNA biopsy. Specificity, sensitivity, positive/negative predictive values, and accuracy of standard cytological examination and galectin-3 immunodetection were assessed. RESULTS: Among cystic papillary carcinomas, 29 of 32 samples were galectin-3 positive, whereas standard FNA cytology made a correct diagnosis in only 25 of 32 samples. All the benign cysts were negative for galectin-3. In comparing the sensitivity and specificity of the two methods, it appeared that both had a 100% specificity, whereas the sensitivity of cytological examination alone was 75% versus 89.3% obtained by galectin-3 immunohistochemistry. CONCLUSIONS: Galectin-3 immunostaining represents a valid pre-operative adjunct to pick up malignant cells in those cases where a very poor number of epithelial cells may lead to a cytological misdiagnosis. Therefore, we suggest that in poorly cellular FNA biopsies of simple or complex thyroid cysts, galectin-3 expression by epithelial cells is consistent with a cystic carcinoma and supports surgical treatment indication.
GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats
Authors: Wickman A , Jonsdottir IH , Bergstrom G , Hedin L
Published: January 2005

OBJECTIVE: This study explored whether short-term replacement therapy with growth hormone (GH) affects blood pressure (BP), heart rate (HR) and endothelial nitric oxide synthase (eNOS) expression in cardiovascular tissues in hypophysectomized (Hx) female rats. DESIGN AND METHODS: BP, HR and the expression of eNOS in the aorta, caval vein and heart were studied in Hx female rats and in Hx female rats that underwent 7 days treatment with GH and thyroxine+glucocorticoids ([T(4)+GC]). Insulin-like growth factor-I (IGF-I) was included in a second experimental protocol to explore the indirect effect of GH. The expression and localisation of eNOS was analysed by immunoblotting and immunohistochemistry. RESULTS: Decreased BP (Hx 98+/-1, Intact 129+/-3 mmHg, P<0.05), HR (Hx 297+/-14, Intact 399+/-31 beats/min, P<0.05) and unchanged eNOS expression was demonstrated in Hx compared with intact rats. None of the hormones affected BP, but both GH and IGF-I increased HR compared with Hx rats (GH 358+/-10, IGF-I 337+/-7, Hx 306+/-11 beats/min, P<0.05). Replacement of GH, GH+[T(4)+GC] and IGF-I resulted in an increased aortic eNOS expression (GH 161+/-24, GH+[T(4)+GC] 177+/-25, IGF-I 153+/-21, Hx 109+/-7%, P<0.05), whereas in caval vein only GH+[T(4)+GC] affected eNOS expression. None of the hormones changed the level of eNOS in the heart. eNOS was localised in the intima layer of the aorta, whereas in the caval vein eNOS was localised in all cell layers. CONCLUSIONS: These findings support the suggested positive role of GH in the regulation of the cardiovascular homeostasis. The observed up-regulation of eNOS, and presumably an increased NO bioavailability, may result in improved endothelial and cardiovascular function.
Growth hormone protects against radiotherapy-induced cell death
Authors: Madrid O , Varea S , Sanchez-Perez I , Gomez-Garcia L , De Miguel E , Gomez De Segura IA , Perona R
Published: January 2005

BACKGROUND: In vivo treatment with growth hormone reduces radiation-associated mortality. The molecular mechanisms underlying this effect are unknown. It has been described that increased sensitivity to ionising radiation can be due to defects in machinery involved in detection and/or repair of DNA double-strand breaks. OBJECTIVE: To study the mechanisms involved in growth hormone action on the increased survival in irradiated cells. MATERIALS AND METHODS: CHO-4 cells stably expressing the growth hormone receptor were used. A cell viability assay was carried out to analyse the increase in survival induced by growth hormone in irradiated cells. To investigate whether the DNA repair mechanism could be implicated in this effect we performed DNA reactivation assays using pHIV-LUC and pCMV-betagal plasmids as control. Identical studies were also conducted using the radiomimetic drug, bleomycin. RESULTS: Growth hormone protects CHO-4 cells from bleomycin- and radiation-induced cell death. In pHIV-LUC transfected cells, a time-dependent decrease in luciferase activity was observed after irradiation in the absence of growth hormone. However, cells pretreated with this hormone maintained reporter activity. When cells were transfected with irradiated pHIV-LUC plasmid, only the hormone-treated cells recovered the transcriptional activity. CONCLUSIONS: Growth hormone exerts a radioprotective effect in CHO-4 cells stably transfected with the complementary DNA for the rat growth hormone receptor. The radioprotection is triggered directly by the hormone and it is also observed with bleomycin. The increased survival in response to radiation and bleomycin treatment induced by growth hormone correlates with an enhanced ability of the cells to repair damaged DNA.
Efficacy of 1400 W, a novel inhibitor of inducible nitric oxide synthase, in preventing interleukin-1beta-induced suppression of pancreatic islet function in vitro and multiple low-dose streptozotocin-induced diabetes in vivo
Authors: Rydgren T , Sandler S
Published: January 2005

OBJECTIVE: Nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS), has been implicated in beta-cell destruction in type 1 diabetes. In the present study, we tested a highly selective iNOS inhibitor, 1400 W, against interleukin-1beta (IL-1beta) induced suppression of rat pancreatic islets, and investigated whether 1400 W could prevent multiple low-dose streptozotocin (MLDS) induced diabetes in mice. Furthermore, we studied if 1400 W affected lipopolysaccharide (LPS) induced increase in plasma nitrite+nitrate (NO(x)) in mice. DESIGN AND METHODS: Precultured rat pancreatic islets were exposed for 48 h to 0, 1, 10 or 50 micromol/l 1400 W in the presence or absence of 25 U/ml IL-1beta, whereupon islet functions were analyzed. MLDS-treated mice were given 5.9 mg/kg body weight of 1400 W intraperitoneally daily or 14 mg/kg body weight twice a day. Blood glucose was monitored and degree of pancreatic mononuclear infiltration was determined. Mice previously injected intraperitoneally with LPS (500 microg) were given 1400 W (14 mg/kg body weight) intraperitoneally and plasma NO(x) was determined after 3, 6 and 10 h. RESULTS: The inhibitor alone did not affect islet functions. 1400 W (50 micromol/l) fully counteracted both the suppression of glucose oxidation rate, (pro)insulin biosynthesis and nitrite accumulation caused by IL-1beta. Cytokine-induced decrease in medium insulin accumulation and glucose-stimulated insulin release was partly counteracted by 1400 W, suggesting that inhibition of insulin release was partially NO independent. LPS-induced increase in plasma NO(x) was markedly inhibited for up to 10 h after 1400 W administration. Irrespective of 1400 W treatment, animals treated with MLDS developed hyperglycemia and pancreatic insulitis. CONCLUSIONS: 1400 W counteracted IL-1beta-induced suppression of rat islets in vitro and LPS induction of NO(x) in vivo, however, it failed to protect against MLDS diabetes in vivo. The latter might be due to a failure by 1400 W in vivo to inhibit NO formation at the level of the pancreatic islet.
Parental genomic imprinting in endocrinopathies
Authors: Polychronakos C , Kukuvitis A
Published: January 2005

Genomic imprinting is the phenomenon whereby some genes preferentially produce mRNA transcripts from the gene copy derived from the parent of a specific sex. It has been implicated in a number of human diseases (most of them of endocrine interest), such as Prader-Willi/Angelman syndromes, Silver-Russell syndrome, Beckwith-Wiedemann syndrome, transient neonatal diabetes, the focal form of nesidioblastosis, and pseudohypoparathyroidism. Involvement of imprinted genes affecting birth weight and causing susceptibility to type 1 diabetes is under investigation. Recent knowledge about the varied molecular mechanisms involved will be outlined.
Resistin - a mediator of obesity-associated insulin resistance or an innocent bystander?
Authors: Ukkola O
Published: January 2005

The objective of this review is to summarize the current evidence of a novel adipocytokine, resistin. Resistin is a novel peptide hormone that belongs to a family of tIssue-specific resistin-like molecules originally named for its resistance to insulin. Although a seminal proposal by Steppan et al. suggested resistin to be a hormone that links obesity to diabetes, several studies have subsequently been published supporting the concept that insulin resistance and obesity are actually associated with a decreased resistin expression. Resistin expression is regulated by a variety of agents and hormones, including thiazolidinediones, insulin, tumor necrosis factor alpha and growth hormone. Studies about their role in the regulation of resistin expression are, however, inconsistent in many cases. Experiments in humans have shown no differences in resistin expression between normal, insulin-resistant or type 2 diabetic samples. However, some recent genetic studies have demonstrated an association between resistin and insulin resistance and obesity. In addition, regional variation in the expression of resistin mRNA and protein levels in humans is an interesting finding with the highest levels found in the abdominal depot. In conclusion, resistin is a fascinating new hormone for which a definite role in metabolism will be revealed in the near future.