bluuebunny/crossref_metadata_2025 huggingface dataset:
Fine-needle aspiration biopsy of the thyroid in an area of endemic goitre: influence of restored sufficient iodine supplementation on the clinical significance of cytological results
Authors: Slowinska-Klencka D , Klencki M , Sporny S , Lewinski A
Published: January 2005

OBJECTIVE: The iodine status of the population of Poland has markedly improved over the past years. The aims of this paper were: (i) to examine the diagnostic value of fine-needle aspiration biopsy (FNAB) of the thyroid in goitre endemic regions (in conditions of improved iodine supply), and (ii) to find whether the changes in iodine supply have already influenced the clinical interpretation of cytological results. METHODS: Cytological diagnoses, based on 3782 aspirates, obtained from 3572 patients during the years 1985-1999, were verified by reference to the results of postoperative examinations. The relative occurrences of selected cytological results in 1992-1999 were also compared (patients not subjected to surgery were included). RESULTS: We have found that the frequency of neoplastic lesions significantly decreased throughout the examined period (P<0.02). The ratio of the papillary carcinoma frequency to the follicular carcinoma frequency increased from 1.7 during 1992-1993 up to 8.0 during 1998-1999 (P<0.05). The frequency of cytologically diagnosed chronic thyroiditis increased from 1.5% in 1992 to 5.7% in 1999 (P<0.001); the percentage of cytological diagnosis of "follicular neoplasm" decreased during the same time (P<0.001). The risk of malignancy significantly lowered in the cytological diagnoses of "follicular neoplasm" from 15% during 1985-1993 to 6% during 1996-1999 (P<0.05). CONCLUSIONS: The diagnostic value of FNAB during the period without proper iodine prophylaxis did not differ significantly from that during the last examined period. However, the changes in iodine supply have markedly and promptly affected the clinical significance of particular cytological results.
Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy
Authors: Daumerie C , Ludgate M , Costagliola S , Many MC
Published: January 2005

Pretibial myxedema (PTM), mainly characterized by the accumulation of glycosaminoglycans in the dermis and subcutaneous tissue, is an extrathyroidal manifestation of autoimmune Graves' disease (GD), almost always associated with Graves' ophthalmopathy (GO). The thyrotropin receptor (TSH-R) has been proposed as the common target antigen in GD, GO and PTM, with evidence for receptor transcripts and/or protein in these locations. The aim of this study has been to investigate whether receptor protein is present in the pretibial tissues. Skin biopsies were obtained from two patients with PTM and two normal subjects without thyroid disease. A portion of each sample was fixed to produce semi-thin sections for Toluidine Blue or Periodic Acid Schiff (PAS) staining. The remainder was snap frozen to generate cryostat sections for immunohistochemical analysis using three monoclonal antibodies against TSH-R. In the skin from the two patients suffering from PTM, the dermis was infiltrated by inflammatory cells (lymphocytes, B cells, macrophages, mast cells) and adipocytes. The collagen fibers were dissociated by edema and by the accumulation of a PAS-positive material. Immunodetection of TSH-R produced positive staining on cells localized in the dermis, beneath the epidermis or close to the hypodermis. These cells were elongated and resembled fibroblasts. No immunoreactivity was observed in the dermis from control patients without thyroid disease. In conclusion, we have evidence for TSH-R immunoreactivity in the pretibium of patients with GD, GO and PTM. Further studies are needed to unambiguously identify the positive cells and determine whether the reactivity is due to the receptor itself or to a cross-reacting protein.
The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa
Authors: Munoz MT , Morande G , Garcia-Centenera JA , Hervas F , Pozo J , Argente J
Published: January 2005

OBJECTIVE: Profound osteopenia is a serious complication of anorexia nervosa (AN). The aim of this work was to study the effect of prolonged AN on lumbar spine bone mineral density (BMD) and to determine whether oral estrogen administration prevents bone loss in women with this disorder. SUBJECTS AND METHODS: Thirty-eight amenorrheic women with AN (mean age: 17.3 years) were treated with estrogen (50 microg of ethinyl estradiol) and gestagen (0.5 mg of norgestrel) during 1 year. Clinical variations, biochemical indices and BMD were studied at three different time points, including after a period of amenorrhea of at least 12 months (n=38), after the administration of estrogens for 1 year (n=22), and after a 1-year follow-up period (n=12). RESULTS: Initial mean BMD was significantly lower than normal (-2.1+/-0.8 s.d.) and less than -2.5 s.d. below normal in 38% of the women with AN. The estrogen-treated group had no significant change in BMD even after the follow-up period and partial recovery of weight. Estradiol and total IGF-I levels were significantly lower throughout the study. All subjects had normal thyroxine (T(4)) and TSH levels and calcium metabolism. However, total tri-iodothyronine (T(3)) was decreased in all anorexic subjects in the first and second study points and were within normal limits after the follow-up period. CONCLUSIONS: (1) Estrogen replacement alone cannot prevent progressive osteopenia in young women with AN. (2) Other factors, such as the loss of weight, the duration of the amenorrhea and the low levels of total insulin-like growth factor-I (IGF-I) could contribute to the loss of bone mass in women with this disorder.
Increased risk of osteoporotic fractures in patients with Cushing's syndrome
Authors: Vestergaard P , Lindholm J , Jorgensen JO , Hagen C , Hoeck HC , Laurberg P , Rejnmark L , Brixen K , Kristensen LO , Feldt-Rasmussen U , Mosekilde L
Published: January 2005

OBJECTIVE: To evaluate if fracture risk was increased in patients with Cushing's syndrome due to the increased endogenous cortisol production. DESIGN: Cohort. METHODS: A self-administered questionnaire was mailed to 125 patients with Cushing's syndrome diagnosed between 1985 and 1999 in Denmark. The response of each patient was compared with that of three age- and gender-matched control subjects randomly drawn among respondents to the same questionnaire from the background population. RESULTS: One hundred and four patients (83%) responded. The median age of the patients was 48 years (range 19-85 years). Sixty-eight had pituitary disease, 28 had adrenal disease, four had had both pituitary and adrenal surgery while four had not undergone surgery at the time of the study. The median time from diagnosis to surgery was 0.2 (range 0-3) years. Eighty-six percent were cured following surgery. There was an increased fracture risk within the last 2 years prior to diagnosis (incidence rate ratio 6.0, 95% confidence intervals (CI): 2.1-17.2). More than 2 years prior to diagnosis and following diagnosis there was no difference in fracture risk between patients and controls. The patients had more low-energy fractures than the controls (relative risk 5.4, 95% CI: 1.4-20.1). There was no difference in fracture risk between patients with adrenal or pituitary disease. CONCLUSIONS: Patients with Cushing's syndrome had an increased fracture risk in a narrow time interval before diagnosis, while no increase in fracture risk could be demonstrated after diagnosis and treatment.
A comparative study of the int-2 gene product in primary and secondary parathyroid lesions
Authors: Tseleni-Balafouta S , Thomopoulou G , Lazaris ACh , Koutselini H , Davaris PS
Published: January 2005

OBJECTIVE: The family of fibroblast growth factors stimulates proliferation of cells of mesenchymal, epithelial and neuroectodermal origin. One of the members of this family, the product of proto-oncogene int-2, fibroblast growth factor-3, has been found to stimulate mitosis of parathyroid cells in culture. Primary and secondary hyperparathyroidism have no clear differences with regard to the histopathological features of the diseased parathyroid glands. DESIGN: This study was undertaken in order to determine whether int-2 protein is immunohistochemically expressed in normal and abnormal parathyroid glands and to investigate whether there is a differential expression of the int-2 gene product between primary and secondary parathyroid disease. METHODS: A sheep anti-human int-2 antibody was applied to tissue sections from 37 samples of primary parathyroid disease (12 sporadic adenomas, 25 hyperplastic glands), from 30 samples of renal hyperparathyroidism, and from seven normal controls. Int-2 immunostaining was evaluated semi-quantitatively. RESULTS: None of the normal parathyroid glands stained positively. Int-2 immunopositive expression was more frequently detected in specimens of uraemic patients than in those of patients with primary parathyroid growth processes (P=0.029). The reason for this differential expression appears to be the higher proportion of oxyphilic cells growing in hyperplastic glands of patients with secondary hyperparathyroidism; the latter cells were specifically found to be int-2 immunoreactive. CONCLUSION: The int-2 gene product is likely to participate in the proliferation of this parathyroid cell subpopulation.
Development of overt Cushing's syndrome in patients with adrenal incidentaloma
Authors: Barzon L , Fallo F , Sonino N , Boscaro M
Published: January 2005

OBJECTIVE: The natural course of adrenal incidentalomas, especially those with subclinical autonomous glucocorticoid production, i.e. subclinical Cushing's syndrome, and the risk that such conditions will evolve towards overt Cushing's syndrome are unknown. DESIGN: Longitudinal follow-up evaluation of a series of 284 consecutive patients with adrenal incidentaloma. METHODS AND RESULTS: Out of 284 consecutive patients with adrenal incidentaloma studied at our Institution in the last 15 years, 98 patients (23 with subclinical hypercortisolism) underwent surgery. Of 130 non-operated patients with a follow-up of at least 1 year, eight had subclinical hypercortisolism at diagnosis. We describe in detail four patients who developed overt Cushing's syndrome after 1-3 years of follow-up. Only one of these patients had subclinical hypercortisolism at first diagnosis. Estimated cumulative risk for a non-secreting adrenal incidentaloma to develop subclinical hyperfunction was 3.8% after 1 year and 6.6% after 5 years. For patients with masses with subclinical autonomous glucocorticoid overproduction, estimated cumulative risk to develop overt Cushing's syndrome was 12.5% after 1 year. CONCLUSIONS: In patients with adrenal incidentalomas the risk of progression towards overt Cushing's syndrome is not low, at variance with previous reports. A careful biochemical and hormonal follow-up is advisable in all patients who do not need surgery at first presentation.
Growth hormone deficiency and replacement in hypopituitary patients previously treated for acromegaly or Cushing's disease
Authors: Feldt-Rasmussen U , Abs R , Bengtsson BA , Bennmarker H , Bramnert M , Hernberg-Stahl E , Monson JP , Westberg B , Wilton P , Wuster C
Published: January 2005

OBJECTIVE: To compare baseline characteristics in adult patients with growth hormone (GH) deficiency (GHD) who had previously been treated for Cushing's disease or acromegaly with data from patients with GHD of other aetiologies. To study the effects of GH therapy in those patients who had completed at least 6 months of GH replacement. DESIGN: Data from a large outcomes research database (KIMS (Pharmacia International Metabolic Database)). METHODS: 135 patients were identified with previous Cushing's disease, 40 had had acromegaly, and 1392 had GHD of other aetiologies. The number of additional hormone deficiencies, and the mean age of the patients were similar in the three groups. Similar proportions of patients in each group were treated using surgery, but radiotherapy was used more often in patients with acromegaly than those with other diagnoses. RESULTS: At baseline, the prevalence of diabetes mellitus and hypertension were significantly higher in the group treated for Cushing's disease, and the prevalence of stroke was significantly higher in the group treated for acromegaly. The incidence of coronary heart disease and claudication were similar in all three groups. Patients treated for Cushing's disease had lower bone mineral density and suffered fractures more often than other GHD adults. Body mass index, waist-hip ratio, serum concentrations of lipids and standard deviation scores of serum concentrations of insulin-like-growth factor-I were similar in the three groups. The dose of GH administered was comparable in the three groups and the effects of GH replacement on waist circumference, blood pressure and quality of life were also similar across the groups. The numbers and types of adverse events reported were not different between the groups. CONCLUSIONS: These data suggest that the characteristics of patients in these diagnostic groups depend on the primary disease which resulted in GHD, and that the clinical expression of GHD does not differ between the groups. Patients with previous hypercortisolism showed more long-term effects of their disease, such as diabetes mellitus, hypertension and fractures. A benefit from GH replacement was evident in patients previously treated for acromegaly and Cushing's disease particularly in relation to quality of life.
Early postnatal treatment of hypogonadotropic hypogonadism with recombinant human FSH and LH
Authors: Main KM , Schmidt IM , Toppari J , Skakkebaek NE
Published: January 2005

BACKGROUND: Patients with hypogonadotropic hypogonadism may be diagnosed shortly after birth because of micropenis and cryptorchidism, combined with subnormal LH and FSH concentrations during the postnatal period. OBJECTIVE: To investigate whether treating these patients with gonadotropins postnatally, to mimic the physiological development, would improve testicular growth and fertility potential later in life. DESIGN: Our patient presented with micropenis. Serum hormone concentrations were measured monthly after delivery: LH and testosterone were undetectable, and FSH and inhibin B were below the normal range (0.05-0.17 IU/l and 79-112 pg/ml respectively). METHODS: From 7.9 to 13.7 months of age, the patient was treated with recombinant human LH and FSH in doses of 20 and 21.3 IU s.c. twice weekly respectively. RESULTS: During treatment concentrations of LH, FSH, inhibin B and estradiol increased to values within normal limits (0.7-1.88 IU/l, 0.17-3.24 IU/l, 121-268 pg/ml and 40-55 pmol/l respectively), whereas serum testosterone remained undetectable. Penile length increased from 1.6 to 2.4 cm and testicular volume, assessed by ultrasound, increased by 170%. No significant adverse events were observed. CONCLUSIONS: Gonadotropin treatment in an infant with hypogonadotropic hypogonadism succeeded in inducing an increase in inhibin B and testicular growth.
Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report
Authors: Winkelmann J , Pagotto U , Theodoropoulou M , Tatsch K , Saeger W , Muller A , Arzberger T , Schaaf L , Schumann EM , Trenkwalder C , Stalla GK
Published: January 2005

OBJECTIVES: The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists. DESIGN: Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease. METHOD: A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques. RESULTS: Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem. CONCLUSION: This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.
IGF-I and GH stimulate Phex mRNA expression in lungs and bones and 1,25-dihydroxyvitamin D(3) production in hypophysectomized rats
Authors: Zoidis E , Gosteli-Peter M , Ghirlanda-Keller C , Meinel L , Zapf J , Schmid C
Published: January 2005

OBJECTIVE: X-linked hypophosphatemia, a renal phosphate (Pi)-wasting disorder with defective bone mineralization, is caused by mutations in the PHEX gene (a Pi-regulating gene with homology to endopeptidases on the X chromosome). We wondered whether changes in Phex and neprilysin (NEP) (another member of the family of zinc endopeptidases) mRNA expression could be observed in relation to vitamin D and Pi metabolism during GH- and IGF-I-stimulated growth of hypophysectomized rats. DESIGN: Animals were infused s.c. for 2 days with vehicle, 200 mU (67 microg) GH or 300 microg IGF-I/rat per 24 h. We determined serum osteocalcin and osteocalcin mRNA in bone, Phex mRNA in bone and lungs, serum 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) and serum Pi levels, and renal expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase), of 25-hydroxyvitamin D(3)-24-hydroxylase (24-hydroxylase) and of the Na-dependent Pi-cotransporter type I and II (Na(d)Pi-I and -II). RESULTS: As compared with vehicle-treated controls, body weight and tibial epiphyseal width significantly increased in GH- and IGF-I-treated animals. Serum osteocalcin and osteocalcin mRNA levels in bone, Phex mRNA in bone and lungs, serum 1,25-(OH)(2)D(3) and renal 1alpha-hydroxylase mRNA rose concomitantly, whereas expression of NEP in lungs was barely affected and renal 24-hydroxylase mRNA decreased. Na(d)Pi-I and -II gene expression in the kidney and serum Pi levels remained unchanged. CONCLUSIONS: Our findings suggest a coordinate regulation of Phex mRNA expression in lungs and bone and vitamin D metabolism during GH- and IGF-I-stimulated growth.
Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice
Authors: Carlsson PO , Karlsson E , Mulder H , Gebre-Medhin S
Published: January 2005

OBJECTIVE: Several biological activities have been ascribed to islet amyloid polypeptide (IAPP). However, their physiological relevance remains unclear. Previous studies in rats with exogenous administration of IAPP suggest that the peptide may increase splanchnic vascular resistance and redistribute the blood flow within the pancreas to the islets. In this study, the use of IAPP-deficient mice allowed us to evaluate possible effects of the lack of IAPP on splanchnic blood perfusion and we could thereby circumvent the potentially pharmacological actions of exogenously administered IAPP. DESIGN: Regional splanchnic blood flow was measured after exogenous administration of IAPP and in IAPP-deficient mice. METHODS: Blood flow values were determined using a non-radioactive microsphere technique in anesthetized animals. RESULTS: No differences in whole pancreatic blood flow or islet blood flow could be detected in IAPP-deficient mice when compared with control mice; neither did IAPP deficiency affect the glucose-induced increase in islet blood flow. Duodenal, ileal and colonic blood flows were similar in IAPP-deficient and control mice. Exogenous administration of IAPP selectively increased islet blood flow in wild-type control mice. CONCLUSIONS: The present findings in the IAPP-deficient mice suggest that the vascular effects seen in the islets after exogenous administration of IAPP to normal mice reflect pharmacological, rather than physiological effects of the peptide. We conclude that the lack of endogenous IAPP within the splanchnic vascular system does not alter the blood perfusion of pancreatic islets or other splanchnic organs.
Epitope mapping of cytochrome P450 cholesterol side-chain cleavage enzyme by sera from patients with autoimmune polyglandular syndrome type 1
Authors: Liiv I , Teesalu K , Peterson P , Clemente MG , Perheentupa J , Uibo R
Published: January 2005

OBJECTIVE: Autoimmune polyglandular syndrome type 1 (APS-1) is a disease associated with defects of the autoimmune regulator gene and is characterized by autoimmune lesions of several tissues, predominantly endocrine glands, with multiple autoantibodies. In this study we describe autoantigenic epitopes on cholesterol side-chain cleavage enzyme (P450scc) using sera from Finnish and Sardinian patients with APS-1, and analyze the epitope reactivities during disease follow-up. METHODS: A series of P450scc cDNA fragments were expressed in E. coli and tested by immunoblotting assay using the patients' sera. RESULTS: Epitope regions were found over the whole P450scc molecule except the last N- (amino acids (aa) 1-40) and C-termini (aa 456-521). The strongest reactivity with patients' sera was found with central and C-terminal regions of the P450scc protein. All studied patients had IgG1 subclass antibodies. CONCLUSIONS: The results show that Finnish and Sardinian patients with APS-1 have similar, polyclonal immune reactions against P450scc, and that epitope reactivities did not change during the disease course. These results support the opinion that autoantibodies against P450scc and their epitope reactivity pattern are formed at an early stage of steroidogenic autoimmunity.
Growth hormone affects both adiposity and voluntary food intake in old and obese female rats
Authors: Malmlof K , Din N , Johansen T , Pedersen SB
Published: January 2005

OBJECTIVE: To investigate whether the promotion of breakdown of body fat and the increased energy expenditure associated with growth hormone (GH) affect the voluntary food intake of an obese organism. DESIGN: Wistar rats (15 months old) were first fed either a high-fat (HF) or a low-fat (LF) diet for 10 weeks. In the subsequent treatment period, two saline groups continued with either the HF or the LF diet, and rats of three other groups had their diet shifted from HF to LF and were treated with saline, human GH (hGH) or rat GH (rGH). hGH and rGH were given in a dose of 4 mg/kg per day. After 21 days of treatment and registration of food intake, rats were killed, blood was collected and tissues were excised. RESULTS: The HF diet produced a significant (P<0.05) increase in weight of fat pads compared with the LF diet: 69+/-5 g compared with 48+/-2 g. The switch from HF to LF diet combined with injections of saline alone decreased the intake of metabolizable energy, but fat pad weight did not decrease significantly (69+/-5 g compared with 63+/-6 g). The latter value was significantly (P<0.05) decreased (to 37+/-3 g) in groups treated with either hGH or rGH. Both GH treatments increased serum IGF-I and muscle weight, whereas the activity of adipose tissue lipoprotein lipase decreased significantly (P<0.01). During the first 9 days of treatment, food intake was significantly (P<0.01) depressed, from 27+/-1 g/kg per day in control rats to 14+/-2 and 16+/-4 g/kg per day in the hGH and rGH groups respectively. CONCLUSION: This study demonstrates that breakdown of adipose tissue and a transient decrease in voluntary food intake are parallel consequences of GH treatment in old and obese rats, and that the actions of hGH and rGH are very similar.
Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood
Authors: Hui H , Perfetti R
Published: January 2005

Pancreas duodenum homeobox-1 (PDX-1) (also known as insulin promoter factor-1, islet/duodenum homeobox-1, somatostatin transactivating factor-1, insulin upstream factor-1 and glucose-sensitive factor) is a transcription factor encoded by a Hox-like homeodomain gene. In humans and other animal species, the embryonic development of the pancreas requires PDX-1, as demonstrated by the identification of an individual with pancreatic agenesis resulting from a mutation that impaired the transcription of a functionally active PDX-1 protein. In adult subjects, PDX-1 is essential for normal pancreatic islet function as suggested by its regulatory action on the expression of a number of pancreatic genes, including insulin, somatostatin, islet amyloid polypeptide, the glucose transporter type 2 and glucokinase. Furthermore, heterozygous mutations of PDX-1 have been linked to a type of autosomal dominant form of diabetes mellitus known as maturity onset diabetes of the young type 4. The dual action of PDX-1, as a differentiation factor during embryogenesis and as a regulator of islet cell physiology in mature islet cells, underscores the unique role of PDX-1 in health and disease of the human endocrine pancreas.
Bone mineral content and bone metabolism during physiological GH treatment in GH-deficient adults--an 18-month randomised, placebo-controlled, double blinded trial
Authors: Sneppen SB , Hoeck HC , Kollerup G , Sorensen OH , Laurberg P , Feldt-Rasmussen U
Published: January 2005

OBJECTIVE: To evaluate the effect of physiological adult growth hormone (GH) replacement on bones. DESIGN: Thirty-six prospective severely growth hormone-deficient (GHD) adults (22 females and 14 males) were randomised to either 18 months of GH (0.03 mU/kg/day) or placebo treatment. METHODS: Bone mineral density and content (BMD, BMC) and body composition were evaluated by dual energy X-ray absorptiometry at baseline and after 6, 12 and 18 months. Serum concentrations of insulin-like growth factor-I (IGF-I), IGF binding protein 3, osteocalcin, carboxyterminal propeptide of type I collagen, carboxyterminal crosslink telopeptide of type I collagen, amino-terminal propeptide of type III procollagen and urine pyridinolin and deoxypyridinolin were determined. RESULTS: IGF-I levels increased from 63.2 microg/l (+/-10.1) to 193.6 (+/- 25.8) microg/l (mean (+/-s.e.)) (P<0.001 compared with placebo). Markers of bone turnover increased significantly from 142% to 227% of baseline values (all P<0.001 compared with placebo). Body composition changes were an increase of lean body mass and a decrease of fat mass resulting in a reduction of percentage body fat of +/- 1.8 (+/- 3.8) in the GH-treated group vs an increase of 1.0 (+/-2.9)) in the placebo-treated group (P=0.002). CONCLUSIONS: No significant difference in BMD or BMC between the GH and placebo groups was found after 18 months. At several sites the variances of changes from baseline were significantly greater in the GH than in the placebo group, indicating an impact of the treatment. From baseline to 6 months an insignificant reduction of total BMD was seen while an increase of BMD was found from 6 to 18 months in the GH group compared with the placebo group.This placebo-controlled trial confirmed the longer term open studies on the effect on bones in patients with GHD, with an initial overrepresentation of bone resorption followed by an increase in BMD which at 18 months had reached baseline level.
The role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH release in normal subjects
Authors: Hanew K , Utsumi A
Published: January 2005

OBJECTIVE: The role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH secretion was studied in man using a GHRH antagonist (GHRH-Ant). DESIGN: Ten healthy adult males were studied for serum GH responses to arginine or insulin singly, or sequentially 120 min after GHRH injection with or without combined administration of GHRH-Ant. Further, GHRH, clonidine or l-dopa were sequentially administered to these subjects 120 min after the GHRH injection. RESULTS: The combined administration of GHRH-Ant distinctly inhibited the arginine- and insulin-induced GH release. When these four agents were sequentially administered 120 min after GHRH injection, the GH responses to clonidine and l-dopa disappeared completely while clear responses were observed to arginine and insulin administration. These responses to arginine and insulin were also completely inhibited by the combined administration of GHRH-Ant. CONCLUSIONS: These results indicate that clonidine and l-dopa stimulate GH secretion mainly through the release of hypothalamic GHRH, and that arginine- and insulin-induced hypoglycaemia stimulate GH secretion mainly through the inhibition of hypothalamic somatostatin release. However, the presence of endogenous hypothalamic GHRH seems to be essential for the maximal stimulation of GH release induced by arginine and insulin.
Ghrelin drives GH secretion during fasting in man
Authors: Muller AF , Lamberts SW , Janssen JA , Hofland LJ , Koetsveld PV , Bidlingmaier M , Strasburger CJ , Ghigo E , Van der Lely AJ
Published: January 2005

OBJECTIVES: In humans, fasting leads to elevated serum GH concentrations. Traditionally, changes in hypothalamic GH-releasing hormone and somatostatin release are considered as the main mechanisms that induce this elevated GH secretion during fasting. Ghrelin is an endogenous ligand of the GH secretagogue receptor and is synthesized in the stomach. As ghrelin administration in man stimulates GH release, while serum ghrelin concentrations are elevated during fasting in man, this increase in ghrelin levels might be another mechanism whereby fasting results in stimulation of GH release. DESIGN AND SUBJECTS: In ten healthy non-obese males we performed a double-blind placebo-controlled crossover study comparing fasting with and fasting without GH receptor blockade. GH, ghrelin, insulin, glucose and free fatty acids were assessed. RESULTS: While ghrelin levels do not vary considerably in the fed state, fasting rapidly induced a diurnal rhythm in ghrelin concentrations. These changes in serum ghrelin concentrations during fasting were followed by similar, profound changes in serum GH levels. The rapid development of a diurnal ghrelin rhythm could not be explained by changes in insulin, glucose, or free fatty acid levels. Compared with fasting without pegvisomant, fasting with pegvisomant did not change the ghrelin rhythm. CONCLUSIONS: These data indicate that ghrelin is the main driving force behind the enhanced GH secretion during fasting.
Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D
Authors: Arlt W , Fremerey C , Callies F , Reincke M , Schneider P , Timmermann W , Allolio B
Published: January 2005

OBJECTIVE: Standard treatment in hypoparathyroidism consists of calcium and vitamin D (or vitamin D analogs) but does not employ replacement of the actual missing hormone. Only few studies have evaluated the efficacy of calcium/vitamin D treatment in hypoparathyroidism; the impact of chronic hypoparathyroid disease on well-being has not been investigated previously. DESIGN: Cross-sectional, controlled study in 25 unselected women with postsurgical hypoparathyroidism since 6.4plus minus8.0 years (s.d.) on stable treatment with calcium and vitamin D (or analogs) and in 25 controls with a history of thyroid surgery but intact parathyroid function, who were matched for sex, age and time since surgery. METHODS: Assessment of well-being and mood using validated questionnaires (the revised version Symptom Checklist 90 (SCL-90-R); the Giessen Complaint List (GBB-24); and the von Zerssen Symptom List (B-L Zerssen)), serum and urinary calcium/phosphorus homeostasis, and in the hypoparathyroid patients also screening for secondary disease by kidney ultrasound, ophthalmological split lamp examination, and measurement of bone mineral density. RESULTS: Serum calcium was in the accepted therapeutic range in the majority of hypoparathyroid patients. However, calcium/phosphorus homeostasis as a whole was clearly non-physiological. Nephrolithiasis was detected in 2 and cataracts in 11 of 25 hypoparathyroid patients. As compared with controls, hypoparathyroid patients had significantly higher global complaint scores in GBB-24 (P=0.036), B-L Zerssen (P=0.002) and SCL-90-R (P=0.020) with predominant increases in the subscale scores for anxiety, phobic anxiety and their physical equivalents. CONCLUSIONS: Current standard treatment in hypoparathyroidism is not only associated with an altered calcium/phosphorus homeostasis but also fails to restore well-being in these patients. Future studies need to address the impact of more physiological treatment options like parathyroid hormone(1-34) or parathyroid transplantation on well-being and mood in these patients.
Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia?: Long-term follow-up of four cases
Authors: Lamas C , Alfaro JJ , Lucas T , Lecumberri B , Barcelo B , Estrada J
Published: January 2005

OBJECTIVE: ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome. Bilateral adrenalectomy is considered the treatment of choice, but the patient is obliged to receive lifetime steroid replacement therapy and is susceptible to adrenal insufficiency crisis. New therapeutic alternatives are being proposed as new etiopathological features of the disease are known. Unilateral adrenalectomy of the largest gland can be a safe and effective alternative, but only short-term follow-up is reported in the literature. We present four consecutive patients with ACTH-independent macronodular hyperplasia and long-term remission of Cushing's syndrome after unilateral adrenalectomy. SUBJECTS: Four consecutive patients (two males and two females, mean age 50.3 years) with Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia underwent unilateral adrenalectomy of the largest gland. RESULTS: The weight of the resected glands ranged from 26.8 to 210 g. Two patients suffered transient post-surgical adrenal insufficiency and had steroid replacement therapy for 60 and 14 months respectively. After a mean follow-up of 78.8 months (range 30-137 months) all the patients persist without any evidence of Cushing's syndrome. Urinary free cortisol and serum cortisol, after the adrenal insufficiency stage, have always stayed within their normal ranges, but cortisol circadian rhythm and suppressibility after dexamethasone have never normalized. No further enlargement of the contralateral gland has been documented 62 to 126 months after surgery in three of the four patients. CONCLUSIONS: Unilateral adrenalectomy can be an effective and safe alternative treatment for ACTH-independent macronodular adrenal hyperplasia, and can achieve long-term remission of Cushing's syndrome.
Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion
Authors: Egido EM , Rodriguez-Gallardo J , Silvestre RA , Marco J
Published: January 2005

OBJECTIVE: Ghrelin is a 28 amino acid residue peptide identified in both human and rat stomach and which acts as an endogenous ligand for the GH secretagogue receptor (GHS-R) and stimulates GH release. GHS-Rs are expressed in a number of tissues, including the pancreas, and ghrelin-like immunoreactivity is present in peripheral plasma, where its levels increase during fasting and decrease after food intake. The relationship between nutritional status and circulating ghrelin concentrations prompted us to investigate the effect of this peptide on pancreatic hormone secretion. METHODS: The study was performed in the isolated rat pancreas perfused in situ. Insulin, glucagon and somatostatin were measured by radioimmunoassay. RESULTS: Addition of 10 nM ghrelin to the perfusate significantly reduced the insulin response to the secretagogues glucose, arginine and carbachol, which act on the B-cell via different mechanisms, as well as the somatostatin response to arginine. Ghrelin was without effect on the glucagon output induced by this amino acid. At a lower concentration (2 nM) ghrelin was also found to inhibit glucose-induced insulin release. CONCLUSION: These findings support the proposal that the inhibitory effect of ghrelin on insulin release constitutes a tonic regulation of the B-cell, contributing to restrain its secretory activity in the state of food deprivation. On the other hand, the inhibition of pancreatic somatostatin release by ghrelin suggests a blocking effect of this hormone on the widely distributed D-cell population.
Effects of pair-feeding and growth hormone treatment on obese transgenic rats
Authors: Furuhata Y , Hirabayashi K , Yonezawa T , Takahashi M , Nishihara M
Published: January 2005

BACKGROUND: It has been shown that GH-deficient subjects tend to have fat accumulation. We have produced human GH (hGH) transgenic rats that exhibit low circulating hGH levels and hyperphagia. These rats are also characterized by severe obesity, hyperinsulinemia and hyperlipidemia. OBJECTIVE: The present study was conducted in order to elucidate how excess caloric intake and impaired GH secretion account for fat accumulation and metabolic abnormalities in the transgenic rats. DESIGN AND METHODS: The transgenic rats were subjected to either pair-feeding with non-transgenic controls or hGH treatment from 4 to 12 weeks of age, and the effects on fat accumulation and some metabolic parameters were assessed. RESULTS: At the age of 12 weeks, body weight and food intake were greater in transgenic than in control rats by 10% and 27% respectively. The ratio of epididymal white adipose tissue weight to body weight (WAT/BW) was more than three times greater in transgenic than in control rats. Although pair-feeding for 8 weeks decreased body weight, it did not affect the WAT/BW ratio. Treatment with hGH affected neither body weight nor food intake, while it reduced the WAT/BW ratio by 30%. Serum concentrations of triglyceride, free fatty acid, insulin and leptin were all significantly higher in the transgenic than in the control rats. Pair-feeding decreased serum triglyceride, insulin and leptin levels, but not serum free fatty acid levels. On the other hand, hGH treatment decreased only serum leptin concentrations. CONCLUSIONS: These results suggest that severe fat accumulation in the transgenic rats mainly resulted from the decreased lipolytic action of GH, while metabolic abnormalities mainly resulted from excess caloric intake.
Postnatal endotoxin exposure results in increased insulin sensitivity and altered activity of neuroendocrine axes in adult female rats
Authors: Nilsson C , Jennische E , Ho HP , Eriksson E , Bjorntorp P , Holmang A
Published: January 2005

OBJECTIVES: Severe postnatal infection leads to a systemic inflammatory response with release of cytokines and glucocorticoids, representing a stressful event for the newborn child. The purpose of this study was to mimic this situation and to study the effects of early postnatal endotoxin exposure of female rat pups on metabolic, endocrine and anthropometric variables in adulthood. DESIGN: Female pups were given subcutaneous injections of lipopolysaccharides (LPS; Salmonella enteriditis, 0.05 mg/kg) or vehicle 3 and 5 days after birth. RESULTS: Six hours after injection, LPS-treated rats had higher corticosterone levels than controls. As adults, LPS-exposed female rats showed increased insulin sensitivity (P<0.05), measured with the hyperinsulinemic euglycemic clamp (5 mU/kg per min). They exhibited a higher locomotor activity (P<0.05) and increased skeletal muscle mass in comparison with controls (P<0.05). Basal ACTH and corticosterone levels in LPS-treated rats were elevated (P<0.05), as were corticosterone levels after exposure to a novel environment stress (P<0.05). The adrenals were morphologically changed and enlarged (P<0.05) in LPS-exposed rats at 11 weeks of age, and a higher density of hypothalamic but not hippocampal glucocorticoid receptor protein was found in the LPS-treated rats (P<0.05). Furthermore, circulating progesterone levels were lower (P<0.05) and testosterone tended to be higher. CONCLUSION: The results indicate that postnatal exposure to LPS leads to increased insulin sensitivity in the adult female rat. In addition, LPS-treated rats showed changes in the regulation of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. This study suggests that postnatal exposure to an endotoxin such as LPS can induce specific programming of neuroendocrine regulation, with long-term consequences in adult life.
Effects of leptin on gonadotropin secretion in juvenile female rat pituitary cells
Authors: Tezuka M , Irahara M , Ogura K , Kiyokawa M , Tamura T , Matsuzaki T , Yasui T , Aono T
Published: January 2005

OBJECTIVE: Leptin is an adipocyte-derived hormone, which is the product of the obese gene and it is thought to play important roles in pubertal development and maintenance of reproductive function in the female. In a study using adult male or female rats, it was found that leptin stimulated the secretion of gonadotropin directly from the pituitary in a dose-related manner. However, there is no study in juvenile female rats before puberty. METHODS: In this study, we cultured pituitary cells from 4-, 6- and 8-week-old female Wistar rats with leptin (0-10(-7)mol/l) and gonadotropin-releasing hormone (GnRH) (0 or 10(-8) mol/l). Basal or GnRH-stimulated secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and their synthesis within cells were determined by radioimmunoassay (RIA). RESULTS: Leptin induced bell-shaped dose--response curves of basal LH and FSH secretion from cultured cells of every age-group of rats studied. The most effective concentration of leptin on the basal secretion of LH and FSH from 6- and 8-week-old cultured pituitary cells was 10(-10) mol/l. This leptin concentration was consistent with circulating physiological serum leptin levels at each age. As for juvenile 4-week-old pituitary cells, the most effective concentration was 10(-11) mol/l which was lower than that of 6- and 8-week-old rats. It was consistent with the circulating serum leptin levels of 4-week-old rats. Also, the synthesis and the GnRH-stimulated secretion of LH and FSH were effectively controlled by leptin at concentrations similar to the serum leptin levels of given ages. CONCLUSIONS: Leptin induced pituitary cells to synthesize and secrete both LH and FSH regardless of the presence or absence of GnRH. The concentration of leptin that induced the greatest synthesis and secretion of gonadotropins from pituitary cells changed around the pubertal period. The most effective leptin concentrations in each experiment were similar to the physiological serum leptin level at each animal age. These results indicate that leptin stimulates gonadotrophs not only in the pubertal and the mature period but also in the juvenile period before puberty. It is also conceivable that leptin may modulate the sensitivity of gonadotrophs until the appearance of GnRH stimulation, and may be the factor that brings about puberty onset.
Interactive effects of growth hormone and oestrogen on vascular responses in hypophysectomised female rats
Authors: Gustafsson H , Tordby AW , Brandin L , Hedin L , Jonsdottir IH
Published: January 2005

OBJECTIVE: Growth hormone (GH) and oestrogen (E(2)) are associated with beneficial effects on the cardiovascular system and it is therefore of great interest to study their interactive effects on haemodynamics and vascular function. DESIGN AND METHODS: Female hypophysectomised (Hx) rats were treated for seven days with GH, E(2) or a combination of the hormones. Systolic blood pressure (SBP), heart rate (HR) and plasma insulin-like growth factor-I (IGF-I) were measured. Contractile properties and endothelial function were studied in isolated resistance arteries using the wire-myograph technique. RESULTS: Hypophysectomy, per se, caused a fall in SBP and HR, while vascular adrenergic reactivity (sensitivity to applied noradrenaline) was enhanced. Impaired acetylcholine-induced relaxation and basal release of nitric oxide, suggests endothelial dysfunction after Hx. After supplementation with GH, SBP remained low while HR increased towards the control level. GH increased plasma IGF-I, but had no effect on vascular contractility or endothelial responses. E(2) replacement resulted in blunted plasma IGF-I, while the vascular adrenergic and serotonergic responses were reinforced. Endothelial function was not improved after E(2) treatment. When GH and E(2) were given in combination, the GH-induced increase in body weight, plasma IGF-I levels and HR were counteracted by E(2). Moreover, the anticipated reinforcement of the vascular serotonergic response by E(2) was reduced. Neither E(2) nor GH+E(2) affected SBP. CONCLUSIONS: The results suggest that GH and E(2) might have interactive effects on haemodynamic and metabolic parameters, but not on the contractility or endothelial function of resistance arteries, in Hx female rats.
Effect of a six-month treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly
Authors: Colao A , Marzullo P , Lombardi G
Published: January 2005

OBJECTIVE: To evaluate the effect of a 6-month treatment with slow-release lanreotide (LAN) on cardiovascular risk and atherosclerosis in 24 normotensive patients with active acromegaly (GH=67.4 +/- 12.6 mU/l, IGF--I=866.0 +/- 55.8 microg/l) and 24 healthy subjects sex-, age- and body mass index-matched with the patients (as controls). DESIGN: Open, prospective, multicenter. METHODS: The following were measured before and after 6 months of LAN treatment (dose 60-90 mg/month): fasting GH, IGF-I, LDL, HDL and total cholesterol, triglyceride, glucose, glycosylated hemoglobin, insulin and fibrinogen levels, intima-media thickness (IMT) and blood systolic and diastolic peak velocity (SPV and DPV respectively) in both common carotids. RESULTS: At study entry, insulin, total and LDL cholesterol, triglyceride and fibrinogen levels were higher while HDL cholesterol levels were lower in patients than in controls. At the right (0.88 +/- 0.04 vs 0.77 +/- 0.03 mm, P=0.05) and left (0.93 +/- 0.03 vs 0.78 +/- 0.02 mm, P=0.01) common carotid IMT was significantly higher in patients than in controls; 12 patients and two controls showed an IMT of > or = 1 mm (chi(2)=8.2, P=0.004). After 6 months of LAN treatment, disease control was achieved in 15 patients (62.5%). Insulin, triglyceride and fibrinogen levels were significantly decreased, and a trend toward a decrease of IMT in the right (from 0.90 +/- 0.05 to 0.78 +/- 0.04 mm, P=0.06) and left (from 0.95 +/- 0.04 to 0.84 +/- 0.04 mm, P=0.06) common carotid arteries was observed only in patients with disease control, while SPV and DPV did not change. CONCLUSIONS: LAN treatment for 6 months significantly lowered GH, IGF-I, insulin and fibrinogen levels and reduced IMT of both common carotid arteries in normotensive patients with acromegaly.