bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid leptin decrease in immediate post‐exercise recovery
Authors: Duclos M. , Corcuff J.‐B. , Ruffie A. , Roger P. , Manier G.
Published: March 2003

OBJECTIVE

Leptin concentrations in humans are known to decrease in response to fasting. The aim of this work was to investigate whether leptin levels might also be modified by exercise‐induced negative energy balance.

SUBJECTS

Eight male runners reported in the morning from 0800 to 1200 h for (i) one resting session (sitting) and (ii) one exercise‐and‐rest session (2 h run and 2 h rest).

MEASUREMENTS

Plasma leptin, free fatty acids (FFA), glycerol, cortisol and salivary cortisol were assayed in both sessions at 1200 h.

RESULTS

After exercise‐and‐rest the leptin concentrations were lower than after rest (1.7 ± 0.1 vs 2.5 ± 0.2 μg/l, P < 0.05), i.e. a mean decrease of 30.3 ± 4.5% (range 9.5–45.8). Plasma FFA, glycerol and cortisol concentrations increased: FFA 0.78 ± 0.08 vs 0.18 ± 0.04 mmol/l, glycerol 0.13 ± 0.01 vs 0.04 ± 0.01 mmol/l, and cortisol 428 ± 36 vs 279 ± 27 nmol/l. A negative correlation was found between plasma FFA and leptin levels (r = − 0.5, P < 0.05) and between plasma glycerol and leptin levels (r = − 0.5, P < 0.05). No correlation was found between leptin and cortisol levels.

CONCLUSIONS

In normal subjects with low body fat, a strenuous exercise‐and‐rest lowers leptin levels by a mean of 30%. A role of lipolysis possibly via increased plasma free fatty acids and glycerol levels is suggested. Cortisol does not seem to be involved.
The impact of gender, puberty and body mass on reference values for urinary growth hormone (GH) excretion in normally growing non‐obese and obese children
Authors: Bona  , Petri  , Rapa  , Conti  , Sartorio
Published: March 2003

OBJECTIVE

There is a lack of normal reference data on urinary GH (u‐GH) excretion in children. We have investigated the impact of age, gender, pubertal development and body mass on reference values for u‐GH excretion in normally growing non‐obese and obese children.

STUDY DESIGN

u‐GH levels were evaluated in 1153 healthy normal children (aged 5–14) and in 684 obese children (body mass index, BMI: > 75th). u‐GH levels (ng/8 h) were determined by ELISA as the mean value of three consecutive first morning voidings.

RESULTS

Reference values (5–95th centile) for u‐GH excretion in obese and non‐obese children of both sexes are reported. In normal prepubertal children median u‐GH levels were relatively stable and superimposable in the two sexes; subsequently, u‐GH levels increased, reaching a peak value at 13 years in both sexes. Significant increments (P < 0.0001) in u‐GH levels were shown at B2 for females and at G3 for males. A slight decline was evident at 14 years. In obese children, median u‐GH concentrations were significantly lower than those recorded in normal children of prepubertal age and at all stages of puberty (except in females at B2), in spite of their comparable normal height. u‐GH levels significantly increased at puberty also in obese children, although the pubertal rise was significantly (P < 0.001) lower (1.7‐fold in both sexes) than that observed in normal children (2.5‐fold in boys and 2.3‐fold in girls). A multiple regression analysis showed that both chronological age (beta: 0.20), BMI (beta: − 0.11), gender (beta: − 0.04) and pubertal stage (beta: 0.25) contributed significantly to the physiological variation in u‐GH levels (multiple R: 0.44, P < 0.00001).

CONCLUSIONS

This study provides reference values for u‐GH in normally growing non‐obese and obese children, analysing the impact of gender, puberty and body mass on this parameter. In agreement with previous studies, which demonstrate blunted GH‐responses to provocative stimuli and reduced nocturnal GH concentration, obese children have significantly lower u‐GH levels than age‐matched normal weight children, both before and during puberty.
Effect of carbenoxolone on the plasma renin activity and hypothalamic–pituitary–adrenal axis in congenital adrenal hyperplasia due to 21‐hydroxylase deficiency*
Authors: Irony Ilan , Cutler Gordon B.
Published: March 2003

OBJECTIVE

To test the hypothesis that carbenoxolone, an inhibitor of 11β‐hydroxysteroid dehydrogenase, might augment the ACTH‐suppressing and mineralocorticoid activities of hydrocortisone without a corresponding increase in peripheral hydrocortisone effects, we assessed the effects of carbenoxolone in patients with congenital adrenal hyperplasia.

DESIGN

AND PATIENTS Six patients with classic 21‐hydroxylase deficiency (5 salt‐losing, 1 nonsalt‐losing) were enrolled in this study. The study protocol involved 3 treatment periods (except for patient 3): phase 1, hydrocortisone and fludrocortisone; phase 2, hydrocortisone, fludrocortisone and carbenoxolone; phase 3, hydrocortisone and carbenoxolone. Patient 3 was not treated with fludrocortisone at baseline, so she participated only in phase 1 (hydrocortisone only) and phase 2 (hydrocortisone and carbenoxolone). Hydrocortisone and fludrocortisone dosages were kept the same during the study except for the discontinuation of fludrocortisone during phase 3.

MEASUREMENTS

Plasma adrenal androgens or their precursors (androstenedione, 17‐hydroxyprogesterone, and testosterone, and urine pregnanetriol); plasma cortisol, cortisol‐binding globulin, ACTH, apparent cortisol metabolic clearance, 24‐h urine 17‐hydroxysteroids, and urine free cortisol; mineralocorticoid activity, as measured by plasma renin activity, body weight, plasma potassium, and mean blood pressure; fasting insulin/glucose ratio, protein balance, % eosinophils in peripheral blood, and total urine pyridinoline and deoxypyridinoline; TRH stimulation of TSH and pyridostigmine/GHRH stimulation of growth hormone.

RESULTS

Compared to phase 1, the addition of carbenoxolone (with or without concurrent fludrocortisone administration) produced statistically significant decreases of 20–50% in mean plasma 17‐hydroxyprogesterone, androstenedione, and renin activity. Since carbenoxolone also decreased the apparent metabolic clearance rate of cortisol by 20%, other measures of systemic glucocorticoid activity were examined. Carbenoxolone did not produce a cushingoid appearance or increase body weight, blood pressure, blood glucose or plasma insulin levels. Carbenoxolone also did not suppress stimulated GH levels, but did decrease TRH‐stimulated TSH levels by approximately 20% (P < 0.05).

CONCLUSION

Carbenoxolone can augment the adrenal androgen‐suppressing activity of hydrocortisone in patients with 21‐hydroxylase deficiency. These observations support the hypothesis that selective inhibition of enzymes that metabolize cortisol may lead to new approaches to improve the treatment of congenital adrenal hyperplasia.
Leptin concentrations in Prader‐Willi syndrome before and after growth hormone replacement
Authors: Myers Susan E. , Davis Ajuah , Whitman Barbara Y. , Santiago Julio V. , Landt Michael
Published: March 2003

OBJECTIVE

This study explored leptin concentrations in Prader‐Willi syndrome (PWS), a genetic disorder characterized by significant obesity and presumed hypothalamic dysfunction. The potential interaction of leptin metabolism with the growth hormone (GH) axis was also studied.

STUDY DESIGN

Plasma leptin concentrations and percent body fat were determined by radioimmunoassay and dual energy x‐ray absorptionmetry, respectively, in 23 children with Prader‐Willi syndrome and 23 children with exogenous obesity.

RESULTS

Log plasma leptin concentrations were positively correlated with percentage body fat in PWS (r = 0.844) and exogenous obesity (r = 0.869). When the regression lines for the two groups were compared, there were no differences in their slopes (P = 0.737) or intercepts (P = 0.701). Administration of recombinant human growth hormone to PWS children for 12 months significantly reduced both percentage body fat and plasma leptin concentrations, but the relationship of log plasma leptin to percentage body fat was unchanged.

CONCLUSION

Prader‐Willi syndrome is not accompanied by deranged leptin concentrations and there was no evidence of an interaction of the GH axis with leptin metabolism in these GH‐deficient children.
Insulin‐like growth factor (IGF)‐1 and IGF‐binding protein‐1 concentrations in serum of normal subjects after alcohol ingestion: evidence for decreased IGF‐1 bioavailability
Authors: Röjdmark  , Rydvald  , Aquilonius  , Brismar
Published: March 2003

OBJECTIVE

Both insulin‐like growth factor (IGF)‐1 and insulin‐like growth factor‐binding protein (IGFBP)‐1 are synthesized by the liver. It is well known that chronic alcohol abuse impairs liver function, but less is known about how an acute intake of moderate quantities of alcohol affects hepatic production of IGF‐1 and IGFBP‐1. The objective of the present investigation was to study this issue by measuring serum levels of IGF‐1 and IGFBP‐1 in normal subjects before, during and after ingestion of a moderate dose of ethanol.

SUBJECTS AND DESIGN

Eight healthy subjects were tested on two occasions. On one occasion (experiment A), three 150‐ml doses of ordinary drinking‐water were given at 08.00, 09.30, and 11.00 h. On another occasion (experiment B), three 150‐ml drinks of diluted ethanol were given instead of water. Each drink contained 0.45 g ethanol/kg b.w. Experiments A and B were performed in random order, 1 week apart. Blood samples were collected before, during and after the drinks over a period of 7 h (08.00–15.00 h). One blood sample was also drawn at 08.00 h the following day.

MEASUREMENTS

Blood glucose and serum concentrations of ethanol, insulin, growth hormone (GH), IGF‐1 and IGFBP‐1 were determined.

RESULTS

When alcohol had been ingested, the serum ethanol concentration rose to a peak value of 28.6 ± 0.9 mmol/l (mean ± SEM). The serum IGF‐1 level declined significantly toward the end of the 7‐h period. The serum IGFBP‐1 level increased promptly in response to ethanol, and reached a maximum 2.7 times above basal as the ethanol level peaked. Neither IGF‐1, nor IGFBP‐1 levels changed significantly after water intake. The IGF‐1 : IGFBP‐1 ratio declined markedly after ethanol (from 15.7 ± 3.9 to 3.9 ± 0.6; P < 0.01), but not after water intake. The blood glucose and serum levels of insulin and GH were unaffected by both ethanol and water.

CONCLUSIONS

Ingestion of moderate amounts of alcohol by healthy individuals results in an acute and profound increase in the serum IGFBP‐1 level and a protracted and less powerful decline in the IGF‐1 level. The mechanism behind the IGFBP‐1 increase is probably a direct effect on the liver, since neither insulin, nor glucose or GH concentrations changed significantly in response to the ethanol challenge.
Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population
Authors: Chang Tien‐Jyun , Lei Hsien‐Hsien , Yeh Jih‐I , Chiu Ken C. , Lee Kuan‐Ching , Chen Mei‐Chu , Tai Tong‐Yuan , Chuang Lee‐Ming
Published: March 2003

OBJECTIVE

Vitamin D and its receptor have been suggested to play a role in the pathogenesis of type 1 diabetes mellitus. We have therefore studied the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes, and rates of glutamic acid decarboxylase (GAD65) autoantibody and islet cell autoantibody (ICA512) positivity.

SUBJECTS

AND MEASUREMENTS One hundred and fifty‐seven type 1 diabetic patients and 248 unrelated normal controls were recruited for this study. Genomic DNA was extracted from peripheral blood leucocytes. All type 1 diabetic patients and controls were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), for three restriction sites in the VDR gene, BsmI, ApaI and TaqI. The χ2 test was used to compare the frequency of the VDR gene polymorphisms in patients and normal controls. The association of VDR gene polymorphisms in type 1 diabetes with the presence of GAD65 and ICA512 autoantibodieswere also examined using the χ2 test.

RESULTS

The allele frequency of the BsmI and ApaI polymorphisms, but not TaqI polymorphism, differed between patients and controls (BsmI P = 0.015; ApaI P = 0.018; TaqI P = 0.266). However, after correction for the three different polymorphisms tested, only the BsmI was significant (pc = 0.045).

CONCLUSIONS

Vitamin D receptor gene polymorphisms were associated with type 1 diabetes in a Taiwanese population. However, functional studies are needed to establish the role of the vitamin D receptor in the pathogenesis of type 1 diabetes mellitus.
Establishment of reference values for standard dose short synacthen test (250 μg), low dose short synacthen test (1 μg) and insulin tolerance test for assessment of the hypothalamo–pituitary–adrenal axis in normal subjects
Authors: Gonzálbez  , Villabona  , Ramón  , Navarro  , Giménez  , Ricart  , Soler
Published: March 2003

OBJECTIVE

To assess the integrity of the hypothalamo–pituitary–adrenal(HPA) axis, many authors have proposed the short synacthen test (ACTH1–24, Tetracosactrin) as a replacement for the insulin tolerance test (ITT). The aim of this study was to compare the plasma cortisol response obtained with both short synacthen tests (high dose (HDT, 250 μg) and low dose (LDT, 1 μg)) with the peak reached during the ITT in healthy volunteers, and to establish the plasma cortisol cut‐off level in each test.

SUBJECTS AND METHODS

Thirty healthy subjects (16 F, 14 M), mean age 34 years, underwent both short synacthen tests. Twenty healthy subjects, 15 of whom (11 F, nine M) belonged to the above group, mean age 30 years, underwent an ITT. Plasma cortisol was measured using a chemiluminiscence immunoassay.

RESULTS

There were no differences between plasma cortisol 30 minutes after both short synacthen tests (HDT: 684 ± 123, LDT: 669 ± 119 nmol/l) and the peaks reached with the LDT (691 ± 123 nmol/l) and the ITT (673 ± 99 nmol/l).The only difference (P < 0.001) was found in the comparison of plasma cortisol peak reached with the HDT (802 ± 142 nmol/l) with the other tests. Plasma cortisol levels obtained in the 5th percentile in each test were: at + 30 minutes: (HDT: 537, LDT: 489 nmol/l), peak: (HDT 649, LDT 498, ITT: 539 nmol/l).

CONCLUSIONS

Comparison of the plasma cortisol response at + 30 minutes with both short ACTH tests and the peak in the insulin tolerance test did not reveal differences. Each test, for each time point and for each biochemical method, requires its own minimum threshold of normality to assess the hypothalamo–pituitary–adrenal axis.
Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH
Authors: Ishii Tomohiro , Ogata Tsutomu , Sasaki Goro , Sato Seiji , Kinoshita Ei‐ichi , Matsuo Nobutake
Published: March 2003

We report a 30‐year‐old female with adrenal unresponsiveness to ACTH. Her clinical features included no adrenal crisis despite poor drug compliance, poor pubic hair development (Tanner stage 2), well‐developed breasts (Tanner stage 5), and regular menstrual cycles. Endocrinological data included blood ACTH 1500 pmol/l, cortisol 18 nmol/l, dehydroepiandrosterone sulphate below 0.26 μmol/l, activated renin 0.37 pmol/l, and aldosterone 3.4 nmol/l. Direct sequencing and allele‐specific amplification revealed two novel mutations in the ACTH receptor gene. One was transition from guanine to adenine at nucleotide position 1002, resulting in substitution of aspartate for asparagine at codon 103, and the other was transition from cytosine to thymine at nucleotide 1104, leading to substitution of arginine for tryptophan at codon 137. The present findings lend additional credence to the notions that adrenal androgens play an important role in female pubic hair development and that ovarian development takes place independently of adrenarche.
Simultaneous peripubertal onset of multireactive autoimmune diseases with an unusual long‐lasting remission of type 1 diabetes mellitus
Authors: Valerio Giuliana , Iovino Adriana Franzesé, Andrea , Tanga Michela , Alessio Maria , Pignata Claudio
Published: March 2003

Although it is well known that patients with type 1 diabetes mellitus are susceptible to other autoimmune diseases, the simultaneous occurrence of clustered distinct autoimmune diseases is uncommon. We report a 16‐year‐old girl, previously diagnosed as having coeliac disease and IgA deficiency, who at 13 years of age developed a clustering of distinct autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis (RA) and euthyroid autoimmune thyroiditis, eventually resulting in a simultaneous long‐term remission. The clinical picture was associated with a functional immunodeficiency characterized by a defect in proliferative responses to T cell predominant mitogens and a normal response to the B cell predominant mitogen. In addition, the T cell activation markers HLA‐DR, IL‐2 receptor and transferrin receptor) were not upregulated. The clinical course of this immunodeficiency paralleled the outcome of the autoimmune diseases. After the abrupt onset, spontaneous clinical remission of both diabetes mellitus and RA was observed. Insulin was first reduced in dose and then discontinued completely at 15 months, in the presence of normal C peptide secretion and normal metabolic control (HbA1c 5.8%). Anti‐glutamate decarboxylase (GAD65) and anti‐IA‐2 antibodies remained persistently high. During the remission phase a normalization of the functional immune defect was observed. The gradual resolution of the multisystemic diseases as well as the normalization of immune function in our patient is unusual. This case may be of considerable value in furthering our knowledge of the immunological mechanisms implicated in these rare multireactive syndromes.
Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction
Authors: Aversa A. , Isidori A. M. , De Martino M. U. , Caprio M. , Fabbrini E. , Rocchietti‐March M. , Frajese G. , Fabbri A.
Published: March 2003

OBJECTIVE

Androgens are essential in the maintenance of nitric oxide‐mediated erectile activity in the rat. The objective of the present study was to investigate the role of androgens in regulating trabecular smooth muscle relaxation in the corpus cavernosum in response to vasoactive challenge in men with erectile dysfunction (ED).

DESIGN

Retrospective, double‐blind correlation analyses.

PATIENTS

Fifty‐two impotent patients without confounding risk factors for ED were obtained from a total of 250 undergoing diagnostic evaluation.

MEASUREMENTS

All patients had dynamic colour duplex ultrasound (D‐CDU) and hormonal evaluation for LH, total and free testosterone, SHBG and oestradiol.

RESULTS

Based upon D‐CDU results patients were diagnosed as having arteriogenic (AR, n = 18; mean age 51) or corporeal venocclusive (CVO, n = 13; mean age 49) ED; in other patients (n = 21, mean age 43) a diagnosis of psychogenic (P)‐ED was made by comprehensive psychogenic testing and confirmed by normal D‐CDU results. AR and CVO patients had altered compliance of cavernous arteries recorded by D‐CDU [20–25% lower resistive index (RI) than patients with psychogenic ED], and lower free testosterone (FT) levels than psychogenic patients [42.3 ± 3.5 SE and 49.3 ± 5.2 vs. 75.2 ± 7.6 pmol/l, respectively; P < 0.01]. More important, in all patients there was a strong direct correlation between resistive index values and FT levels (r = 0.47, P = 0.002); the relationship was maintained also when adjusted for age, SHBG and oestradiol (r = 0.37, P = 0.02).

CONCLUSIONS

These results indicate that in men with erectile dysfuntion low free testosterone may correlate independently of age with the impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to a vasoactive challenge. These findings give clinical support to the experimental knowledge of the importance of androgens in regulating smooth muscle function in the penis.
Tall stature in familial glucocorticoid deficiency
Authors: Elias Lucila L. K. , Huebner Angela , Metherell Louise A. , Canas Atilio , Warne Gary L. , Bitti Maria L Manca , Cianfarani Stefano , Clayton Peter E. , Savage Martin O. , Clark Adrian J. L.
Published: March 2003

OBJECTIVE

Familial glucocorticoid deficiency (FGD) has frequently been associated with tall stature in affected individuals. The clinical, biochemical and genetic features of five such patients were studied with the aim of clarifying the underlying mechanisms of excessive growth in these patients.

PATIENTS AND METHODS

Five patients with a clinical diagnosis of FGD are described in whom the disorder resulted from a variety of novel or previously described missense or nonsense mutations of the ACTH receptor (MC2‐R). All patients demonstrated excessive linear growth over that predicted from parental indices and increased head circumference.

RESULTS

Growth hormone and IGF‐I‐values were normal. Growth charts suggest that the excessive growth is reduced to normal following the introduction of glucocorticoid replacement. A characteristic facial appearance including hypertelorism, marked epicanthic folds and prominent frontal bossing was noted.

CONCLUSIONS

These findings indicate that ACTH resistance resulting from a defective ACTH receptor may be associated with abnormalities of cartilage and/or bone growth independently of the GH–IGF‐I axis, but probably dependent on ACTH actions through other melanocortin receptors.
Sweat secretion rates in growth hormone disorders
Authors: Sneppen Simone B. , Main Katharina M. , Juul Anders , Pedersen Lone M. , Kristensen Lars Ø. , Skakkebæk Niels E. , Feldt‐Rasmussen Ulla
Published: March 2003

BACKGROUND

While increased sweating is a prominent symptom in patients with active acromegaly, reduced sweating is gaining status as part of the growth hormone deficiency (GHD) syndrome.

DESIGN AND SUBJECTS

Sweat secretion rate (SSR), as measured by pilocarpine iontophoresis represents the maximal capacity for stimulated sweat secretion in a localized skin area. SSR was studied in 37 patients with a history of acromegaly, 20 adult patients with GHD before and during long‐term GH substitution of GHD adults, and 58 control subjects.

RESULTS

Acromegaly: Patients with acromegaly had significantly higher SSR than healthy controls (Z‐score + 1.9 (± 1.1) mean (± SD) (P < 0.001)). SSR was increased irrespective of current clinical disease activity. Thus, the SSR Z‐scores in 16 clinically inactive patients were + 2.1 (± 1.2), in 10 slightly or doubtfully active patients + 1.5 (± 0.7) and in 11 active patients + 1.8 (± 1.3). There was no correlation between SSR and IGF‐I. GHD: Twenty adult patients participated in an 18‐month randomised, placebo controlled, double blinded study of physiological dose GH substitution, followed by 18 months of open GH treatment. SSR at baseline was reduced in male but not in female GHD patients. Mean SSR (95% confidence interval) for 11 male patients was 89.0 mg/30 minutes (51.9–126.1) as compared to 133.5 mg/30 minutes (59.2–259.9) (P = 0.01) in 24 male controls, and for 11 female patients 48.2 mg/30 minutes (25.9–70.6) as compared to 49.2 mg/30 minutes (12.6–93.9) in 34 female controls. GH treatment in physiological substitution doses for up to 36 months had no effect on SSR.

CONCLUSION

We have demonstrated that longstanding GH hypersecretion in patients with acromegaly induces irreversible changes of sweat gland function, with persistently elevated SSR despite treatment and clinical cure. In GHD patients, SSR was reduced in males but not in females, which together with the established gender difference in normal controls emphasises the role of androgen deficiency as a cofactor for reduced sweating in hypopituitary patients. Sweat gland development seems to be more susceptible to lack of hormones in childhood and adolescence than in adulthood, whereas growth hormone excess can modify sweat function later in life.
Serum α‐subunit levels in patients with pituitary adenomas
Authors: Samejima Naoyuki , Yamada Shozo , Takada Koji , Sano Toshiaki , Ozawa Yasunori , Shimizu Taeko , Usui Masaaki , Shishiba Yoshimasa
Published: March 2003

OBJECTIVE We investigated preoperative and postoperative serum α‐subunit levels and the α‐subunit response to TRH in patients with various types of pituitary tumour and correlated the data with histological findings in order to clarify the significance of α‐subunit measurement in pituitary adenomas.

PATIENTS We examined 59 patients with pituitary tumours (22 with GH cell adenomas, 30 with clinically nonfunctioning adenomas and seven with other tumours) treated at Toranomon Hospital between 1996 and 1998.

RESULTS The basal α‐subunit level was supranormal in six out of 22 (27%) patients with a GH cell adenoma and in nine out of 30 (30%) patients with a nonfunctioning adenoma. A paradoxical α‐subunit response to TRH was found in seven out of 22 (32%) patients with a GH cell adenoma. These seven patients also showed a paradoxical GH response to TRH administration. In addition, paradoxical response to TRH was found in eight out of 30 (27%) patients with a clinically nonfunctioning adenoma. In contrast, patients with other types of pituitary tumour showed neither a supranormal α‐subunit level nor a paradoxical response to TRH. The supranormal α‐subunit level and the abnormal response to TRH were normalized in both GH cell adenoma and nonfunctioning adenoma patients after successful surgery. Immunohistochemical studies showed α‐subunit positive cells in 51% of GH cell adenomas or nonfunctioning adenomas and there was a good concordance with the serum α‐subunit levels in both GH cell adenoma and nonfunctioning adenoma patients.

CONCLUSIONS These findings suggest that supranormal serum α‐subunit levels are mainly due to hypersecretion by the tumour itself, while the paradoxical α‐subunit response to TRH is an associated phenomenon in patients with a GH cell adenoma or nonfunctioning adenoma. The α‐subunit level and the response to TRH may be useful indicators for assessing the operative outcome, especially in nonfunctioning adenoma patients who have no other definite endocrine markers.
Choosing an oestrogen replacement therapy in young adult women with Turner syndrome*
Authors: Guttmann Hadassah , Weiner Zeev , Nikolski Eugenia , Ish‐Shalom Sophia , Itskovitz‐Eldor Joseph , Aviram Michael , Reisner Shimon , Hochberg Ze'ev
Published: March 2003

OBJECTIVE Hormone replacement therapy (HRT) is prescribed to most patients with Turner syndrome (TS) although its use in adult TS patients has not been scientifically evaluated. The present study was performed to compare the short‐term effects in adult women with Turner syndrome of low‐dose oral conjugated oestrogen (0·625 mg, CE) with relatively high dose ethinyl oestradiol (30 µg, EE2); both combined with an oral progestin.

DESIGN and PATIENTS After 4 months off HRT, 17 young, otherwise healthy women with TS were enrolled in a random, unblinded, crossover study of the two oestrogenic preparations, each given for 6 months.

MEASUREMENTS We compared parameters of oestrogenic activity that would cover immediate changes in hormone levels, biochemistry, bone turnover, uterine and cardiac variables, which constitute risk factors for later development of diabetes, atherosclerosis, osteoporosis and aortic dissection.

RESULTS Serum FSH returned to normal follicular phase levels only on the EE2 regimen. The hypotrophic endometria normalized with either of the two oestrogen regimens with no excessive hypertrophy. Hyperinsulinaemia was suppressed to normal by both EE2 and CE. PTH and 1,25‐dihydroxyvitamin D levels increased on HRT (EE2 > CE), and phosphorus decreased. Alkaline phosphatase, osteocalcin and urinary deoxypyridinoline cross‐links (DPD) were high off therapy; the former two suppressed to high–normal levels on the EE2 regimen, but not on CE, and DPD did not normalize with either HRT. Lipid profiles in these young TS patients were normal. Liver enzymes were mildly elevated off therapy and suppressed to normal levels on both regimens, but more so with EE2.

CONCLUSIONS The risk factors embodied in hyperinsulinaemia and enhanced bone turnover which, ultimately, have consequences for TS morbidity, are minimized by HRT. In the short term, neither regimen is effective for bone turnover in adult women with Turner syndrome.
Mdm2 and the p53 pathway in human pituitary adenomas
Authors: Suliman Mohamed , Royds Janice , Cullen Derek , Timperley Walter , Powell Tom , Battersby Robert , Jones T. Hugh
Published: March 2003

Studies on pituitary tumours have failed to identify mutations in the tumour suppressor gene p53 suggesting that the protein identified is wild type. p21WAF−1 is a downstream effector of p53 which promotes growth arrest. Mdm2 (mouse double minute) is a protein induced by wild type p53 and forms an autoregulatory feedback loop suppressing wild type p53 activity. The purpose of this study was to examine a group of pituitary tumours for expression of p53 and its two downstream effector proteins p21WAF−1 and mdm2 and to compare this with their radiological invasive status and proliferative potential as assessed by Ki‐67 expression.

Sixty‐nine tumours removed at transsphenoidal surgery were examined by immunocytochemistry using antibodies against p53, p21WAF−1, mdm2 and Ki‐67 (MIB‐1). The invasive status of the tumours was determined from the preoperative CT/MRI scans.

 p53 was expressed in 42 of 69 (61%) pituitary adenomas but there was no relationship with either pituitary tumour invasive status (P = 0·71) or volume (P = 0·33). p53 expression correlated, however, with the proliferative state of the tumours as assessed by the MIB‐1 labelling index (P = 0·0065). Invasive tumours had a higher growth fraction than non‐invasive ones (P = 0·027). p21WAF−1 was expressed in the nuclei of 58/69 (84%) pituitary adenomas and its expression correlated with that of p53 (r = 0·26, P = 0·03). Mdm2 was expressed in the cytoplasm of 46/69 (67%) tumours and this correlated with the nuclear staining for p53 (P = 0·022) while nuclear staining was seen in 32/69 (46%) tumours but this did not correlate significantly with nuclear p53 staining (P = 0·096).

These results suggest that p53, p21WAF−1 and mdm2 are all expressed in pituitary tumours suggesting that the p53 protein detected by immunocytochemistry is wild type. Expression of p53 is associated with tumours which have a higher proliferative status. The p53 activity is probably the result of upstream signals of local stresses mediated through either genetic change, cytokines, hypoxia or hormonal factors. Our results suggest, however, that the downstream pathway mediated through the activities of p21WAF−1 and mdm2 may be dysfunctional in these tumours.
Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy
Authors: Cagnacci Angelo , Arangino Serenella , Angiolucci Marco , Melis Gian Benedetto , Facchinetti Fabio , Malmusi Stefania , Volpe Annibale
Published: March 2003

OBJECTIVE

Several effects of melatonin are modulated by gonadal steroids and are reduced in ageing women. Administration of melatonin reduces internal carotid artery pulsatility index (PI), and blood pressure in young individuals. Whether these effects are conserved in postmenopausal women and are influenced by hormone replacement therapy (HRT), was herein investigated.

DESIGN

Randomised, double‐blind placebo controlled study.

PATIENTS

Twenty‐three postmenopausal women of which 11 were unreplaced with HRT and 12 on the oestrogenic phase of continuous transdermal estradiol (50 µg/day) plus cyclic medroxyprogesterone acetate (5 mg/day × 12 days every 28 days).

MEASUREMENTS

Internal carotid PI, by colour Doppler, and supine blood pressure were evaluated 90, 180 and 240 minutes following the oral administration of melatonin (1 mg) or placebo. Levels of nitrites/nitrates (NOx), the stable derivatives of nitric oxide, were also evaluated in samples collected 90 minutes following the administration of placebo or melatonin.

RESULTS

In women not on replacement therapy melatonin was ineffective. In HRT‐treated women, melatonin reduced internal carotid artery PI (P = 0·005). The effect was maximal within 90 minutes, and maintained for at least 240 minutes, with melatonin levels in the nocturnal physiological range. Systolic and diastolic blood pressures were reduced of 8 mmHg (P = 0·038) and 4 mmHg (P = 0·045), respectively, while NOx levels were significantly increased (P = 0·024).

CONCLUSIONS

The circulatory response to melatonin is conserved in postmenopausal women with but not without hormone replacement therapy. Maintenance of the cardiovascular response to melatonin, may be implicated in the reduced cardiovascular risk of postmenopausal women with hormone replacement therapy.
Central precocious puberty: clinical and laboratory features*
Authors: Chemaitilly Wassim , Trivin Christine , Adan Luis , Gall Valérie , Sainte‐Rose Christian , Brauner Raja
Published: March 2003

To determine whether the initial presentation of patients with central precocious puberty (CPP) varies according to the aetiology, whether this permits the differentiation between idiopathic and organic forms, and whether the body mass index (BMI) and plasma leptin concentrations are linked to gonadotrophin secretion.

The clinical and laboratory features of 256 patients (26 boys and 230 girls) with CPP were studied separately in boys and girls. We compared patients with idiopathic CPP (seven boys and 186 girls) to those with organic CPP, whose pubertal development revealed a central nervous system (CNS) lesion (five boys and 11 girls), and to patients with organic CPP associated with a previously treated CNS lesion (14 boys and 33 girls).

Boys with organic CPP, having revealed or treated CNS lesions, started their puberty earlier (3·0 ± 1·0 years and 6·7 ± 0·5 years) than boys with idiopathic CPP (8·5 ± 0·2 years, P < 0·01 and < 0·05). Boys with organic CPP associated with a treated CNS lesion had lower luteinizing hormone (LH)/follicle stimulating hormone (FSH) peaks ratio after stimulation with gonadotrophin releasing hormone (GnRH) (1·6 ± 0·5) than did boys with idiopathic CPP (2·2 ± 0·3, P < 0·05). Girls with organic CPP revealing a CNS lesion started their puberty earlier (3·6 ± 0·9 years) than girls with idiopathic CPP (6·6 ± 0·1 years, P < 0·0 l) and had higher LH (P < 0·01) and FSH peaks (< 0·05). Girls with organic CPP associated with a treated CNS lesion had higher BMI (1·8 ± 0·2 z‐score) than did girls with idiopathic CPP (1·3 ± 0·1 zs, P < 0·05), higher leptin concentrations (11·7 ± 1·8 µg/l vs. 7·7 ± 0·5 µg/l, P < 0·0 l), LH peak (P < 0·01), FSH peak (P < 0·05) and LH/FSH peaks ratio (1 ± 0·1 vs. 0·8 ± 0·1, P < 0·05). Only 12·4% of the girls with idiopathic CPP had BMI‐zs < 0, and their plasma leptins were positively correlated with BMI (P < 0·0001).

The features of central precocious puberty vary according to the aetiology, but it is impossible to exclude a central nervous system lesion in a given patient with central precocious puberty without performing central nervous system imaging. This imaging remains necessary in all cases of central precocious puberty. Most of the girls with idiopathic central precocious puberty had increased BMI, but we found no correlation between plasma leptin concentrations and gonadotrophin secretion.
Effects of 6 years of growth hormone (GH) treatment on bone mineral density in GH‐deficient adults
Authors: Clanget C. , Seck T. , Hinke V. , Wüster C. , Ziegler R. , Pfeilschifter J.
Published: March 2003

OBJECTIVE Adults with growth hormone (GH) deficiency are often osteopenic. Short‐term GH replacement therapy has been shown to improve bone mineral density (BMD). However, whether the increases in BMD are progressive with time is still unclear. We therefore examined long‐term changes in BMD with GH treatment in GH‐deficient adults over a period of 6 years.

DESIGN  Open prospective GH therapeutic study.

PATIENTS  Twelve GH‐deficient patients (four women, eight men) with a mean age of 42·5 years (range 24–61 years) at the beginning of GH replacement. Eleven patients suffered in addition from LH/FSH insufficiency, eight from TSH insufficiency and eight from ACTH insufficiency. Before the start of GH substitution, the insufficient anterior pituitary axes were fully substituted for an average of 9·8 years (range 2–22 years). Average daily GH dose was 2·4 IU (SD 0·86).

MEASUREMENTS BMD and bone area were measured at annual intervals at the lumbar spine and at the proximal femur using dual‐X‐ray absorptiometry.

RESULTS  Under GH substitution, serum insulin‐like growth factor I concentrations increased by 140 μg/l compared to pretherapeutic values (P = 0·0003). BMD at the lumbar spine increased by 0·16 g/cm2 (P = 0·0005), corresponding to a mean increase of 15·9% or an increase of the BMD Z‐score by 1·53 SD. Increases in BMD were independently observed from years 3 to 6 by a mean of 5·8% (P = 0·0087). This increase was paralleled by an increase in the area of the lumbar vertebrae. Bone area also increased at selected sites of the proximal femur, but there was no consistent increase in BMD at the proximal femur.

CONCLUSION  GH therapy in GH‐deficient adults is able to progressively increase BMD and bone area at the lumbar spine over a period of at least 6 years. However, our study has several limitations, making it necessary to confirm these findings in further long‐term studies.
Alcohol consumption is associated with reduced prevalence of goitre and solitary thyroid nodules
Authors: Knudsen Nils , Bülow Inge , Laurberg Peter , Perrild Hans , Ovesen Lars , Jørgensen Torben
Published: March 2003

OBJECTIVE Goitre prevalence is dependent on iodine intake and smoking habits, but further risk factors have only been examined briefly. We examined the association between alcohol consumption and the prevalence of thyroid enlargement and nodularity.

DESIGN Cross‐sectional population study with ultrasonography of the thyroid gland and assessment of alcohol intake and smoking habits from questionnaires.

SUBJECTS Four thousand six‐hundred and forty‐nine men and women aged 18–65 years, randomly selected from the Danish Civil Registration System.

MEASUREMENTS Thyroid volume and prevalence of thyroid enlargement, multiple nodules or a solitary nodule in the thyroid.

RESULTS Abstainers and participants with a low alcohol consumption (< 7 drinks/week) had the same prevalence of thyroid enlargement and nodularity, but participants with moderate (8–28 drinks/week for women, 8–42 for men) or high (> 28/42 drinks/week) alcohol consumption had much lower prevalence of thyroid abnormalities. Possible confounding by sex, age, iodine status and smoking was considered in all models. Odds ratios compared to abstainers for thyroid enlargement were 0·74 [95% confidence interval (CI) 0·57–0·96] for moderate‐ and 0·44 (95% CI 0·22–0·88) for high alcohol consumption. Odds ratios compared to abstainers for a solitary nodule were 0·64 (95% CI 0·42–0·96) for moderate‐ and 0·41 (95% CI 0·12–1·37) for high alcohol consumption. Mean thyroid volume was 13·5 ml among abstainers compared to 10·9 ml among participants with high alcohol consumption (P < 0·001). Both wine‐ and beer consumption were associated to lower prevalence of thyroid abnormalities.

CONCLUSIONS Increasing levels of alcohol consumption were associated to lower prevalence of thyroid enlargement and to lower prevalence of a solitary nodule in the thyroid, and indications of a causal relationship were found.
Assessment of selective arterial calcium stimulation and hepatic venous sampling to localize insulin‐secreting tumours
Authors: Brändle Michael , Pfammatter Thomas , Spinas Giatgen A. , Lehmann Roger , Schmid Christoph
Published: March 2003

OBJECTIVE Non‐invasive localization modalities such as ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) often fail to localize insulinomas smaller than 2 cm in diameter. Recent studies have shown that the selective arterial stimulation and hepatic venous sampling (ASVS) technique using intra‐arterial calcium as the insulin secretagogue facilitates the regionalization of such occult insulinomas. This study assesses the sensitivity of ASVS in localizing insulin‐secreting tumours.

SUBJECTS AND METHODS Eleven consecutive patients (8 women), aged 29–82 years, were studied over the past 4 years at our hospital. Hyperinsulinaemic hypoglycaemia due to an insulin‐secreting tumour was proven in all patients. Calcium gluconate (0·025 mEq/kg body weight) was injected directly into the arteries supplying the pancreas and the liver. Insulin levels were measured in samples taken from the right hepatic vein before and 30, 60 and 120 s after each injection. The ASVS technique was performed in all 11 patients; the results were compared with the surgical findings in 10 patients and the autopsy findings in 1 case. The ASVS results were also compared with the findings of other, previously performed imaging modalities.

RESULTS ASVS correctly localized 4 insulin‐secreting tumours to the head, 3 to the body, 1 to the tail, 2 to the tail or body of the pancreas and 1 to the liver. Thus, the sensitivity was 100% (11/11) whereas other localization techniques were less sensitive: 7/11 tumours were detected by angiography, 4/8 by endosonography, 3/8 by CT and 1/6 by MRI. Insulinomas (confirmed by histological examination), sized 4–25 mm, were found in 10 patients. All were cured by selective surgery and remained free of hypoglycaemia over the next 1–4 years of follow‐up. An insulin‐secreting neuroendocrine tumour in the liver was documented in 1 case at autopsy.

CONCLUSIONS Arterial stimulation and hepatic venous sampling is a very sensitive technique for preoperative localization of insulin‐producing tumours. It can help to plan minimally invasive surgery and to select an appropriate strategy for patients suffering from malignant tumours in others.
TSH‐receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays
Authors: Pedersen Inge Bülow , Knudsen Nils , Perrild Hans , Ovesen Lars , Laurberg Peter
Published: March 2003

OBJECTIVES Graves' disease is characterized by stimulating autoantibodies to the TSH‐receptor (TRAb). The aim of this study was to compare the performance of a new TRAb assay based on competitive binding to recombinant human TSH‐receptors (H‐TRAb) with an assay employing purified porcine TSH‐receptors (P‐TRAb). Furthermore, to evaluate the applicability of the H‐TRAb assay to discriminate between patients with hyperthyroidism due to Graves' disease (GD) and multinodular toxic goitre (MNTG).

DESIGN AND MEASUREMENTS H‐TRAb and P‐TRAb were measured in patients with newly diagnosed hyperthyroidism due to GD (n = 106) and MNTG (n = 94). For comparison, TRAb was measured in patients with primary autoimmune hypothyroidism, euthyroid subjects with an enlarged thyroid gland by ultrasound, and healthy controls (n = 100 for each group). Patients were consecutively included from a population survey.

RESULTS If the cut‐off values recommended by the manufacturer for TSH‐receptor antibody positivity were used for evaluation, the sensitivity of the H‐TRAb assay vs. the P‐TRAb assay in diagnosing GD was: 95·3/67·9% (P < 0·001). Specificity was (H/P‐TRAb): 99/99%. The sensitivity of P‐TRAb was increased if the upper 97·5% limit of measurements in controls was used as cut‐off (H‐TRAb vs. P‐TRAb: 95·3/80·2%, P < 0·001). Specificity (H/P‐TRAb): 98/98%. The difference between assay performance may partly be due to a better technical performance of the H‐TRAb assay with more reliable results in the low range of measurements. However, even in GD patients with clearly measurable TRAb, 25% had a P‐TRAb < 50% of the value expected from the H‐TRAb measurement. This suggests that a subgroup of patients produce TRAb with a higher affinity for the human than the porcine TSH receptor. A relatively high proportion of patients with MNTG were TRAb positive (H‐TRAb/P‐TRAb: 17/9%). Characteristics of H‐TRAb positive and negative MNTG patients were compared. There was no difference between size of thyroid gland and number of nodules by ultrasonography. H‐TRAb positive patients had significantly higher serum T4 and T3 and a greater number were TPO‐Ab positive.

CONCLUSIONS H‐TRAb diagnosed Graves' disease with a high sensitivity and specificity than P‐TRAb. The high occurrence of TRAb in multinodular toxic goitre might in part reflect an overlap between Graves' disease and multinodular toxic goitre in some patients.
Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women
Authors: Yamauchi Mika , Sugimoto Toshitsugu , Yamaguchi Toru , Nakaoka Daiki , Kanzawa Michiko , Yano Shozo , Ozuru Rieko , Sugishita Takeshi , Chihara Kazuo
Published: March 2003

OBJECTIVE Although total fat body mass (FM) is considered to be one of the major determinants of bone mass, the mechanism by which FM and bone mass are positively correlated remains unclear. Leptin, the product of the obese (ob) gene, is secreted from adipocytes and its plasma levels are known to be positively correlated with %fat (FM divided by total body weight). There is recent evidence suggesting that leptin directly stimulates osteoblastic differentiation. Thus it is possible that the anabolic action of this hormone on bone may participate in the positive correlation between FM and bone mass. In this study, we analysed the relationships between either plasma leptin levels or %fat vs. bone mineral density (BMD) values as well as the presence of vertebral compression fractures, and evaluated whether or not plasma leptin levels were associated with BMD or bone fragility in a manner independent of FM.

PATIENTS One hundred and thirty‐nine postmenopausal women (age 48–78 years, mean 62·5), who visited our outpatient clinic for the evaluation of osteoporosis.

DESIGN and MEASUREMENTS Plasma concentrations of leptin after an overnight fast were measured by radioimmunoassay. BMD values were measured by dual‐energy X‐ray absorptiometry (DXA) at the lumbar spine, femoral neck and whole body. Distal one‐third of radius BMD was measured by single photon absorptiometry (SPA). Vertebral fractures were assessed by lateral thoracic and lumbar spine radiographs.

RESULTS Although neither plasma leptin levels nor %fat correlated with age, there was a significant positive correlation between plasma leptin levels and %fat (r = 0·563, P < 0·001). Plasma leptin levels were significantly and positively correlated with BMD values at all skeleton sites measured, and multiple regression analysis revealed that this positive relationship was still observed with BMD values of the femoral neck and of the whole body, even after %fat and age were taken into account. Moreover, plasma leptin levels but not %fat were significantly lower in women with vertebral fractures than in those without fractures. When multiple logistic regression analysis was performed with either plasma leptin value or %fat employed as independent variables, plasma leptin values but not %fat were selected as an index affecting the presence of vertebral fractures.

CONCLUSION Our study showed that plasma leptin levels but not %fat are associated with BMD and the presence of vertebral fractures in postmenopausal women, suggesting that circulating leptin might play a physiological role in maintaining bone mass as well as better bone quality.