bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased leptin production in vivo and insulin cleavage by the omental adipose tissue of morbidly obese patients
Authors: Cuatrecasas G. , Granada M. L. , Formiguera X. , Rull M. , Alastrué A. , Remesar X. , Alemany M. , Foz M. 
Published: June 2003

OBJECTIVEThe aim of this investigation was to assess the insulin cleavage capacity in obese humans. Increased insulin degradation by visceral adipose tissue has previously been demonstrated in obese rats and could be interpreted as a physiological response to hyperinsulinaemia. The recent characterization of leptin receptors in pancreatic β cells, liver and muscle suggests that leptin may influence insulin function and metabolism. Our study focuses on the possible relationship between leptin secretion and adipose tissue insulin‐degrading capacity.DESIGN AND PATIENTSInsulin and leptin were measured in arterial blood and in the epiploic vein of morbidly obese (n = 7) and non‐obese patients (n = 7) who were undergoing abdominal surgery. Arteriovenous insulin difference (AV insulin) was considered an in vivo marker of insulin degradation by the omental fat tissue. Statistical comparison between venous and arterial leptin was used to assess endogenous leptin production.MEASUREMENTSInsulin was measured using an oligoclonal IRMA and leptin levels were determined by using a specific radioimmunoassay.RESULTSMorbidly obese patients were hyperinsulinaemic compared to non‐obese patients according to arterial insulin levels (P = 0.049) but not to venous levels. Insulin cleavage capacity, nil in the control group, was clearly significant in the morbidly obese patients (P = 0.001). In the morbidly obese group, leptin levels in venous epiploic samples were significantly higher (P = 0.028) than in the arterial samples, confirming in situ the synthesis of leptin by human white adipose tissue. We also observed a correlation between insulin arterial levels and venous leptin concentrations (P = 0.009) which supports the chronic leptinogenic effect of insulin suggested in previous works. Finally, our results show that venous leptin levels are correlated with the extent of insulin cleavage by omental tissue (P = 0.033).CONCLUSIONSMorbidly obese patients have a higher white adipose tissue insulin cleavage capacity, which could partially diminish hyperinsulinaemia‐derived adverse effects. High leptin production, a consequence of high insulin levels, may act as a signal to the insulin‐degrading tissues in order to lower insulinaemia.
Carrier status for steroid 21‐hydroxylase deficiency is only one factor in the variable phenotype of acne
Authors: Ostlere Lucy S. , Rumsby Gillian , Holownia Peter , Jacobs Howard S. , Rustin Malcolm H. A. , Honour John W. 
Published: June 2003

OBJECTIVEPrevious endocrine studies of women with acne have produced diverse results. This study was designed to seek evidence, from endocrine and genetic studies, for impaired steroid biosynthesis in patients with acne.DESIGNAdrenal stimulation tests with synthetic adrenocorticotrophic hormone (ACTH) were performed.MEASUREMENTSSteroid hormones were measured basally and 30 minutes after ACTH. The results were correlated with analysis of the steroid 21‐hydroxylase gene (CYP21).PATIENTSFifty‐one consecutive female patients (mean age 27.1 years) referred with acne.RESULTSThe median plasma 17‐hydroxyprogesterone (17‐OHP) before and 30 minutes after ACTH were 2.5 nmol/l (range 1.1–8.2) and 7.3 (2.1–17.8) nmol/l which were significantly above normal female controls (n = 11, mean age 25.6 years) at 1.5 (0.9–4.2) and 4.6 (2.6–8.4) nmol/l. Eighteen of 51 acne patients showed an abnormal 17‐OHP response. The 21‐hydroxylase gene (CYP21) was examined for major deletions and for three common point mutations in 31 of the patients (14 with exaggerated 17‐OHP response). One patient had a deletion of CYP21 on one allele consistent with carrier status for the classical congenital adrenal hyperplasia (CAH). Five patients, one of whom had a normal 17‐OHP response to Synacthen, were heterozygous for the val 281 leu mutation in exon 7 of the CYP21 and were therefore carriers for a mutation associated with late‐onset CAH. One patient with a raised 17‐OHP response was homozygous for the splice site mutation in intron 2 and one patient with a normal 17‐OHP response was heterozygous for the mutation. None of the patients had the ile 172 asn mutation. Eight of the 31 acne patients who had CYP21 gene analysis were carriers for mutations in the 21‐hydroxylase gene but only six would have been detected by an abnormal response of 17‐OHP on stimulation.CONCLUSIONAlthough alterations of the CYP21 gene were more common in acne than in controls there is a poor correlation between these events and raised steroids and acne. Factors other than mild impairment of CYP21 contribute to the variability of the clinical phenotype in hyperandrogenic states including acne.
Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene
Authors: Hiroi N. , Yakushiji F. , Shimojo M. , Watanabe S. , Sugano S. , Yamaguchi N. , Miyachi Y. 
Published: June 2003

OBJECTIVEActivating mutations of the ACTH receptor have not been previously described. We investigated a 69‐year‐old woman with normal blood cortisol but undetectable blood ACTH concentrations. The aim of this study was to evaluate her hypothalamo–pituitary–adrenal axis by measuring circadian variation in blood ACTH and cortisol, and by performing CRH and ACTH stimulation and dexamethasone suppression tests. We also examined biological activity of her circulating blood ACTH using bovine adrenocortical cell suspensions and ACTH receptor gene structure by Northern blotting analysis.RESULTSRandom plasma cortisol concentrations ranged from 182 to 328 nmol/l, while ACTH concentrations were always undetectable. After an intravenous bolus injection of human CRH 100 μg, plasma ACTH rose slightly, while plasma cortisol increased appropriately. ACTH stimulation tests revealed that a small amount of ACTH (5 ng/kg b.w.) had the maximal cortisol stimulatory activity, and even smaller amounts of ACTH (0.5 and 0.05 ng/kg b.w.) produced significant increases in cortisol levels. ACTH bioassay of the patient's plasma demonstrated weak biological activity in the HPLC fractions which corresponded to the band of synthetic human ACTH 1–39. The ACTH receptor coding region was amplified by polymerase chain reaction using the leucocyte genomic DNA. There were two base mutations; cysteine 21 → arginine and serine 247 → glycine in the sequences coding for the first extramembranous N‐terminal domain and the third extramembranous loop of the ACTH receptor.CONCLUSIONSThis patient with normal blood cortisol but undetectable ACTH levels showed increased adrenocortical sensitivity to ACTH and two point mutations in the ACTH receptor gene. This study, therefore, reports a previously undescribed syndrome—ACTH hypersensitivity syndrome—and provides insights into the molecular mechanism of ACTH receptor action.
The genetics of autoimmune endocrine disease
Authors: Tait Karen F. , Gough Stephen C. L. 
Published: June 2003

SummaryThe common autoimmune endocrinopathies result from an interaction between environmental factors and genetic predisposition. Several chromosomal gene regions have been shown to contribute to more than one disease, supporting the clinical observation that the autoimmune endocrine diseases cluster within individuals and families. Genetic studies have implicated the major histocompatability complex (MHC)‐human leucocyte antigen (HLA) genes on chromosome 6p21, although this chromosomal region does not explain all of the genetic contribution to the various disorders. Non‐MHC‐HLA genes, including disease‐specific loci, are beginning to be identified and the publication of the draft sequence of the human genome will undoubtedly expediate future discoveries. Combined with the establishment of large cohorts of subjects with disease and the development of technology capable of performing high‐throughput genotyping, genetic studies are likely to impact on the future treatment and prevention of the common autoimmune endocrine diseases.
Growth hormone secretory pattern and response to treatment in children with short stature followed to adult height
Authors: Radetti Giorgio , Buzi Fabio , Cassar Walburga , Paganini Claudio , Stacul Elisabetta , Maghnie Mohamad 
Published: June 2003

Summaryobjective To compare the relative utility of GH stimulation tests and assays of spontaneous GH secretion as predictors of change in height standard deviation score at the end of GH treatment in children with short stature.patients and methods We retrospectively studied 116 children (67 boys and 49 girls) with subnormal growth rates and short stature, defined as a height of more than 2SD below the mean for age and sex. The patients were classified according to their pattern of findings on baseline pharmacological GH stimulation tests and a 12‐h assay of nocturnal spontaneous GH secretion. Twenty‐eight patients (24%) had normal hormone levels by both methods (group I); 14 (12%) had normal levels by stimulation tests but subnormal levels by the physiological assay (group II); 48 (41%) had subnormal levels on pharmacological stimulation, with normal physiologic levels (group III); and 26 (22%) had subnormal levels by both methods (group IV). All children in groups II and IV, and 27 in group III, designated IIIb, were treated with recombinant GH at 0·7 U (0·23 mg/kg) of body weight per week. GH secretory patterns were related to final height SD scores and other growth parameters, after the patients had attained their adult stature 6·7 ± 2·2 years (SD) after GH evaluation.results The five groups were similar with respect to mean baseline height SD scores for chronological as well as bone age. Whether assessed as absolute or parentally adjusted (relative) values, mean gains in height SD scores were significantly greater in treated patients with physiologicial hormone deficiency (groups II and IV) than in those with normal hormone levels (group I, untreated controls). Relative height gains were 1·03 ± 1·45 cm (6·6 ± 9·28 cm) and 1·85 ± 1·21 cm (SDS; 11·8 ± 7·74 cm) in groups II and IV respectively, compared with only 0·11 ± 0·42 cm (0·7 ± 2·68 cm) in group I (P < 0·01 and P < 0·001). GH treatment failed to improve either the absolute or parentally adjusted final height of patients with GH deficiency by stimulation tests but normal levels by physiological assay.conclusion Long‐term administration of GH to short children with normal spontaneous GH secretion is not associated with an appreciable increase in adult height.
A novel specific bioassay for the determination of glucocorticoid bioavailability in human serum
Authors: Vermeer H. , Hendriks‐Stegeman B. I. , Van Den Brink C. E. , Van Der Saag P. T. , Van Der Burg B. , Van Buul‐Offers S. C. , Jansen M. 
Published: June 2003

Summaryobjective Some patients develop side‐effects even on relatively low doses of topically administered glucocorticoids (GCs), while others appear to be less sensitive to GCs. We have developed and validated a bioassay which can measure glucocorticoid bioavailability directly from small amounts of human serum to help elucidate underlying mechanisms.methods We have stably transfected the human embryonic kidney cell line HEK293 with a plasmid expressing the glucocorticoid receptor, and a plasmid containing the luciferase gene preceded by three concatenated steroid response elements, bringing luciferase expression under control of the liganded glucocorticoid receptor.results The assay, with an intra‐ and interassay coefficient of variance (CV) better than 10%, showed the expected difference in potency between different GCs (fluticasone propionate > budesonide > dexamethasone > hydrocortisone). No cross‐reactivity was detected with other steroid hormones such as progesterone, testosterone and oestradiol. The bioassay easily detects the rise and subsequent fall of bioavailable GCs in human serum following ingestion of only 0·5 mg dexamethasone, and clearly reflects the diurnal cortisol rhythm. Moreover, systemic availability following inhalation of 2 × 250 µg fluticasone propionate using a pressure dose inhaler could be demonstrated.conclusions This assay can be used to determine levels of bioavailable GCs in serum, both endogenous and administered, and thus may help in optimizing treatment regimens. The small amount of serum needed to perform an analysis makes this assay applicable even to infants.
Diagnostic reliability of a single IGF‐I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency
Authors: Aimaretti G. , Corneli G. , Baldelli R. , Di Somma C. , Gasco V. , Durante C. , Ausiello L. , Rovere S. , Grottoli S. , Tamburrano G. , Ghigo E. 
Published: June 2003

Summaryobjective Within an appropriate clinical context, GH deficiency (GHD) in adults must be demonstrated biochemically by a single provocative test. Insulin‐induced hypoglycaemia (ITT) and GH‐releasing hormone (GHRH) + arginine (ARG) are indicated as the tests of choice, provided that appropriate cut‐off limits are defined. Although IGF‐I is the best marker of GH secretory status, its measurement is not considered a reliable diagnostic tool. In fact, considerable overlap between GHD and normal subjects is present, at least when patients with suspected GHD are considered independently of the existence of other anterior pituitary defects. Considering the time and cost associated with provocative testing procedures, we aimed to re‐evaluate the diagnostic power of IGF‐I measurement.design To this goal, in a large population [n = 237, 139 men, 98 women, age range 20–80 years, body mass index (BMI) range 26·4 ± 4·3 kg/m2] of well‐nourished adults with total anterior pituitary deficit including severe GHD (as shown by a GH peak below the 1st centile limit of normal response to GHRH + ARG tests and/or ITT) we evaluated the diagnostic value of a single total IGF‐I measurement. IGF‐I levels in hypopituitary patients were evaluated based on age‐related normative values in a large population of normal subjects (423 ns, 144 men and 279 women, age range 20–80 years, BMI range 18·2–24·9 kg/m2).results Mean IGF‐I levels in GHD were lower than those in normal subjects in each decade, but not the oldest one (74·4 ± 48·9 vs. 243·9 ± 86·7 µg/l for 20–30 years; 81·8 ± 46·5 vs. 217·2 ± 56·9 µg/l for 31–40 years; 85·8 ± 42·1 vs. 168·5 ± 69·9 µg/l for 41–50 years; 82·3 ± 39·3 vs. 164·3 ± 60·3 µg/l for 51–60 years; 67·5 ± 31·8 vs. 123·9 ± 50·0 µg/l for 61–70 years; P < 0·0001; 54·3 ± 33·6 vs. 91·6 ± 53·5 µg/l for 71–80 years, P = ns). Individual IGF‐I levels in GHD were below the age‐related 3rd and 25th centile limits in 70·6% and 97·63% of patients below 40 years and in 34·9% and 77·8% of the remaining patients up to the 8th decade, respectively.conclusions Total IGF‐I levels are often normal even in patients with total anterior hypopituitarism but this does not rule out severe GHD that therefore ought to be verified by provocative testing of GH secretion. However, despite the low diagnostic sensitivity of this parameter, very low levels of total IGF‐I can be considered definitive evidence of severe GHD in a remarkable percentage of total anterior hypopituitary patients who could therefore skip provocative testing of GH secretion.
Physiological testosterone replacement and arterial endothelial function in men
Authors: Sader Mark A. , Griffiths Kaye A. , Skilton Michael R. , Wishart Susan M. , Handelsman David J. , Celermajer David S. 
Published: June 2003

Summaryobjective The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long‐term physiological androgen replacement therapy, at trough and peak testosterone levels.patients and design  We recruited nine hypogonadal men (aged 35 ± 4 years) receiving androgen replacement therapy, each treated with 800 mg testosterone (T) depot preparations every 6 months.measurements Serum lipid and hormone levels and arterial reactivity were measured, prior to (trough T) and 2–4 weeks following testosterone administration (peak T). Each subject therefore served as their own control. Vessel diameter was measured by ultrasound at rest, during reactive hyperaemia [leading to flow‐mediated dilatation (FMD), an endothelium‐dependent response] and after sublingual nitroglycerin (GTN, an endothelium‐independent dilator).results Serum T (13 ± 2 nmvs. 27 ± 3 nm for trough and peak serum T, respectively, P < 0·001; normal adult male range 11–35 nm), and free T (195 ± 23 pmvs. 510 ± 93 pm, P < 0·005) significantly increased following subcutaneous depot T administration, as did serum oestradiol (100 ± 10 pmvs. 175 ± 9 pm, P = 0·001; normal adult male range < 250 pm). There was a significant decrease in FMD (3·6 ± 1·1%vs. 3·0 ± 0·8%, P < 0·01), but GTN responses were similar (9·5 ± 0·8%vs. 10·4 ± 1·0%, P > 0·2). Lipid, blood pressure and vessel diameter measurements were also similar before and after testosterone administration.conclusion Physiological replacement of testosterone is associated with decreased endothelium‐dependent dilatation, in hypogonadal men.
The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients
Authors: Di Blasio Anna Maria , Van Rossum Elisabeth F. C. , Maestrini Sabrina , Berselli Maria Elisa , Tagliaferri Mariantonella , Podestà Francesca , Koper Jan W. , Liuzzi Antonio , Lamberts Steven W. J. 
Published: June 2003

Summaryobjective  We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low‐dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity.design Two hundred and seventy‐nine patients (mean BMI 45·9 ± 0·9 kg/m2) were genotyped using both PCR‐restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype.results In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2·3%) and had significantly higher BMI (P < 0·04), resting energy expenditure (P < 0·03) and food intake (P < 0·01) when compared to wild‐type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI (P = 0·04), resting energy expenditure (P = 0·03) and food intake (P = 0·008) than obese women with the wild‐type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case–control study with homozygous wild‐type obese subjects which were age‐, sex‐ and BMI‐matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the BclI variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the BclI polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL‐cholesterol levels (P = 0·005 and P = 0·05, respectively).discussion Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the BclI polymorphism as well, tend to have a slightly unfavourable cardiovascular profile.
Assessment of quality of life in adults receiving long‐term growth hormone replacement compared to control subjects
Authors: Malik I. A. , Foy P. , Wallymahmed M. , Wilding J. P. H. , MacFarlane I. A. 
Published: June 2003

Summaryobjective There are few studies of quality of life (QOL) in adults with growth hormone deficiency (GHD) compared to matched control populations without GHD. These have shown impairments in a variety of QOL measures, which improve but do not normalize after short‐term replacement with GH. There is little information on QOL in long‐term treated GHD patients compared with controls without GHD.patients and methods A total of 120 adults with GHD who had received GH replacement for at least 1 year were identified from the neuroendocrine clinic. Patients were asked to complete eight QOL questionnaires and an Energy Visual Analogue Scale (VAS). Results were compared with 83 control subjects without GHD from the local population who agreed to complete seven of the QOL questionnaires (excluding Disease Impact scale) and the energy VAS. The eight questionnaires were a combination of generic and disease‐specific questionnaires used to assess health related QOL, namely: Short Form‐36 (SF‐36), Nottingham Health Profile (NHP), Disease Impact, Life Fulfilment and Satisfaction scales, Mental Fatigue Questionnaire (MFQ) and Self Esteem scale, Hospital Anxiety Depression (HAD) scale and QOL‐AGHDA (assessment of GHD in adults).results Eighty‐nine patients returned questionnaires and 85 (71%) had complete data for analysis. The mean (SD) duration of GH replacement was 36·0 ± 26·4 (range 13–159) months. Mean age was 43·9 ± 15·8 years (37 males) in treated GHD patients compared to a mean age 41·7 ± 10·5 years (32 males) in the controls. Mean IGF‐1 levels were 22·5 ± 13·6 nmol/l in the GHD patients and the mean dose of GH replacement was 1·2 ± 0·4 IU daily. Analysis of the QOL questionnaires from the GH treated patients revealed highly significant impairments in all measures (most P ≤ 0·0001, except life fulfilment‐material, P = 0·33) compared to the control population.conclusions This large population with treated GH deficiency have significant impairments in multiple aspects of QOL despite replacement with GH and other pituitary hormones for at least 1 year (mean 3 years). It is likely therefore that other factors in addition to GH deficiency must influence QOL in these patients. Further strategies to improve QOL in these individuals should therefore be considered, e.g. psychological support and treatments and physical treatments (such as exercise programmes).