bluuebunny/crossref_metadata_2025 huggingface dataset:
Testicular dysfunction in adrenomyeloneuropathy
Authors: Brennemann W , Kohler W , Zierz S , Klingmuller D
Published: January 2005

Adrenomyeloneuropathy (AMN) is a disorder due to a disturbance in the peroxisomal beta-oxidation of saturated very long chain fatty acids. It is characterized by symptoms of the nervous as well as the endocrine systems, especially the adrenal cortex and the gonads. We investigated the testicular function in 49 male AMN patients aged 36.2 +/- 1.5 years (range, 18.5-59 years). Twenty-four of these patients were suffering from adrenocortical insufficiency. Twenty-five AMN patients showed neurological symptoms without 'Addison's disease'. To register the frequency and the degree of gonadal impairment, LH and FSH, testosterone, free testosterone and inhibin-B were determined. Gonadotropin concentrations were significantly higher in AMN patients than in healthy controls (LH, 8.0 +/- 1.2 vs 2.77 +/- 0.11 IU/l; FSH, 10.1 +/- 1.6 vs 4.0 +/- 0.17 IU/l; P < 0.001). Serum LH was elevated in 31 patients (63.3%); 28 patients (57.1%) showed elevated serum FSH indicating deficient spermatogenesis. Mean testosterone did not differ significantly between patients and healthy controls, but mean free testosterone was significantly lower in patients than in controls (16.3 +/- 1.0 vs 28.5 +/- 1.68 pg/ml, P < 0.002). Inhibin-B concentrations did not differ between AMN patients and healthy men. The testosterone/LH ratio reflecting an impairment of the Leydig cells was significantly lower in AMN patients than in controls (P < 0.01). An impairment of the Leydig cells and/or of the Sertoli cells was evident in 81.6% of AMN patients. Twenty-one of thirty-nine patients (53.8%) admitted erectile dysfunction. These data indicate that endocrine dysfunction in AMN is not only confined to adrenocortical functions, but testicular dysfunctions also frequently occur, thus permitting the term 'adreno-testiculo-myelo-neuropathy'.
Final height of patients treated for isolated GH deficiency: examination of 83 patients
Authors: Cacciari E , Cicognani A , Pirazzoli P , Zucchini S , Salardi S , Balsamo A , Cassio A , Pasini A , Carla G , Tassinari D , Gualandi S
Published: January 2005

The aim of the present study was to evaluate retrospectively the influence of various auxological and laboratory parameters on final height in a group of GH-deficient children after replacement therapy and to compare their final height with that of a group of short children with normal GH secretion and hence not treated. The final height was evaluated of 83 patients (51 males and 32 females) affected by idiopathic isolated GH deficiency and treated with recombinant human GH (hGH) for 2-7 years. Inclusion criteria at the start of treatment were short stature (mean height for chronological age in standard deviation score (SDS) -2.21) due to idiopathic isolated GH deficiency (GH peak < 8 micrograms/l after two pharmacological tests and/or mean GH concentration < 3.3 micrograms/l during the night) and treatment with recombinant hGH for at least 2 years at a dose of 15-20 U/m2 per week by s.c. injection for 6 or 7 days/ week. Mean chronological age at diagnosis was 12.2 +/- 1.7 years; 35 were prepubertal and 48 pubertal. The final height of 51 untreated short stature (mean height for chronological age in SDS -2.13 at diagnosis) subjects (42 males and 9 females: 29 prepubertal and 22 pubertal at diagnosis with mean chronological age 11.6 +/- 2.4 years) with normal GH secretion was also evaluated. In the treated subjects final height SDS was higher than that of the untreated group (-1.3 vs -1.7 SDS; P = 0.01). Both treated and untreated subjects showed a final height lower than target height, but 39% of the treated subjects vs only 20% of the untreated group (P = 0.035) had a final height greater than target height. In the treated subjects this percentage was higher in the patients improving their height for bone age in the first years of therapy. While treated females showed a positive correlation only between target and final height (P = 0.0001), in treated males final height correlated with the Bayley-Pinneau prediction at diagnosis, height for chronological age and bone age at diagnosis and target height. Patients who started therapy before puberty also showed these correlations with data calculated at the onset of puberty, together with a correlation with chronological age at the onset of puberty. When considering the influence of GH response at tests on final height, the percentage of subjects exceeding target height increased progressively according to the severity of the GH deficiency. There was no difference in height gain between the patients starting therapy before or during puberty. The height gain, however modest, obtained by our treated patients, the number of patients with final height greater than target height and the favourable comparison with the untreated short-stature subjects represent a promising result, which could be improved by personalizing treatment.
Serum leptin in obesity is related to gender and body fat topography but does not predict successful weight loss
Authors: Niskanen LK , Haffner S , Karhunen LJ , Turpeinen AK , Miettinen H , Uusitupa MI
Published: January 2005

OBJECTIVE: Leptin is the product of the ob gene shown to regulate body fat and appetite in mice. It is produced by human adipose tissue also, but its physiological functions in man are poorly known. STUDY DESIGN AND METHODS: We studied serum leptin concentrations in ten obese men and 35 obese women (age and body mass index 42 +/- 7 years and 35.1 +/- 3.6 kg/m2 respectively) before (baseline) and at 17 and 57 weeks during weight loss of 10.9% of the initial weight. RESULTS: Serum leptin concentrations at baseline were 55% higher in women than in men (after adjustment for age and body fat mass, P = 0.002) and remained so during the follow-up. At baseline, serum leptin correlated with fat mass (r = 0.60, P < 0.001) estimated by bioelectrical impedance, and the changes in leptin concentrations from baseline to week 17 correlated with the changes in fat mass (r = 0.73, P < 0.001), but baseline leptin levels were not predictive of the successful weight loss. Leptin concentrations correlated with hip circumference (r = 0.49, P < 0.001 at baseline adjusted for age and sex), but the correlation with waist circumference became evident only during the weight loss (at week 57, r = 0.63, P < 0.001). CONCLUSIONS: Serum leptin concentrations are higher in obese women than in obese men before and during weight loss, but the topography of fat tissue influences serum leptin concentrations. Serum leptin concentrations do not predict the response to weight reduction.
Serum free insulin-like growth factor-I in growth hormone-deficient adults before and after growth hormone replacement
Authors: Skjaerbaek C , Vahl N , Frystyk J , Hansen TB , Jorgensen JO , Hagen C , Christiansen JS , Orskov H
Published: January 2005

The objective of the present study was to compare fasting levels of free IGF-I in serum from patients with adult onset growth hormone deficiency (GHD) and from healthy volunteers, and to examine the effect of GH replacement therapy in GHD on serum free IGF-I. Free IGF-I was measured using separation of free IGF-I by ultrafiltration in serum samples from 42 healthy volunteers and 27 patients with GHD, in the latter before and after 1 year of treatment with GH (2 IU/m2) (n = 13) or placebo (n = 14). Free IGF-I was significantly decreased in patients with GHD (700 +/- 100 ng/l (mean +/- S.E.M.), range 55-2618 ng/l) compared with controls (1010 +/- 70 ng/l, range 231-2431 ng/l; P = 0.0016). Total IGF-I was 85 +/- 10 micrograms/l (GHD) and 160 +/- 10 micrograms/l (controls) (P < 0.0001). The ratio of free over total IGF-I was increased in GHD to 0.85 +/- 0.08% compared with 0.66 +/- 0.05% in controls (P = 0.04). In both GHD and controls, free IGF-I correlated significantly (P < 0.05) with total IGF-I (GHD r = 0.78; controls r = 0.42), IGFBP-1 (GHD r = -0.67; controls r = -0.46) and the molar ratio of total IGF-I over IGFBP-3 (GHD r = 0.58; controls r = 0.62). After 1 year of GH treatment, free IGF-I was increased to 2780 +/- 320 ng/l (P = 0.003) and total IGF-I was increased to 270 +/- 30 micrograms/l (P = 0.006) both of which values were greater than those in healthy volunteers. There were no changes in free or total IGF-I in the placebo-treated group. In conclusion, levels of free IGF-I are decreased in GHD, but measurements of free IGF-I in a single, fasting serum sample do not offer a better separation of patients with GHD from individuals with normal GH status than can be achieved by measurement of total IGF-I. One year of treatment with 2IU/m2 GH caused an increase of serum free IGF-I to supraphysiological levels.
Relationship between the release of prolactin and endothelin-1 in human decidualized endometrial cells
Authors: Kubota T , Taguchi M , Kobayashi K , Masuda M , Aso T
Published: January 2005

The study was undertaken to investigate the interaction between the release of endothelin-1 (ET-1) and prolactin (PRL) from human decidualized endometrial cells, and the effects of transforming growth factor (TGF)-beta 1 on the release of ET-1 and PRL from human decidual cells in the early stage of pregnancy. Stromal cells derived from human endometrial tissues were cultured on a type-1 collagen membrane in serum-free medium with or without 100 nmol/l oestradiol and 1 mumol/l medroxyprogesterone acetate (MPA) for 12 days. In addition, decidual cells of early pregnancy were cultured with or without TGF-beta 1 for 48 h. PRL and ET-1 levels in the media were measured by a specific enzyme immunoassay and RIA respectively. In decidualized endometrial cells induced by ovarian steroid hormones in vitro, PRL release increased and ET-1 release decreased in a time-dependent manner. Ovarian steroid hormones significantly attenuated ET-1 release. In the decidual cells of early pregnancy, TGF-beta 1 significantly attenuated the PRL release, whereas this growth factor dose-dependently increased ET-1 release. There was a significant negative correlation between the release of PRL and that of ET-1. These results demonstrate that the regulation of PRL release is quite different from that of ET-1 release in the human decidualized endometrial cells, and suggest that TGF-beta 1 has significant effects on PRL and ET-1 release in the human decidua of early pregnancy.
17 beta-Oestradiol inhibits stimulated endothelin release in human vascular endothelial cells
Authors: Wingrove CS , Stevenson JC
Published: January 2005

Oestrogen is believed to possess cardiovascular protective properties. Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen for vascular smooth muscle cells. We have investigated release of ET-1 from human endothelial cells in response to 17 beta-oestradiol. Serum was found to stimulate significantly ET-1 release during the first 4 h of culture. 17 beta-Oestradiol significantly reduced ET-1 immunoreactivity in the media of treated cells by up to 49% of control values after 4 h. This effect was found to be inversely related to the dose of 17 beta-oestradiol. Significant dose-dependent increases in nitric oxide synthase expression were observed in response to oestrogen after 24 h but not after 4 h. Serum-free experiments demonstrated that low doses of oestrogen were able to inhibit thrombin-induced ET-1 release whilst supraphysiological levels did not. These results provide a further perspective on the ability of oestrogens to maintain vascular health.
Plasma bovine pregnancy-associated glycoprotein concentrations throughout gestation in relationship to fetal number in the cow
Authors: Patel OV , Sulon J , Beckers JF , Takahashi T , Hirako M , Sasaki N , Domeki I
Published: January 2005

This study characterized the peripheral plasma bovine pregnancy-associated glycoprotein (bPAG) profile throughout gestation and examined the effect of stage of gestation and fetal number on this profile in Holstein cows after non-surgical embryo transfer. Cows (n = 12) were divided into three groups: group 1 = normal singleton pregnancies (n = 5); group 2 = normal twin pregnancies (n = 5); group 3 = abnormal twin pregnancies (n = 2). Blood was collected about every third day from day 0 (defined as the first day of standing estrus), then daily for the last 10 days of gestation, and sampling was stopped one day postpartum. The time-related changes in plasma bPAG concentrations were significantly (P < 0.01) affected by the stage of gestation and fetal number (P < 0.01), except during the last 10 days of gestation. In both normal pregnancy groups, bPAG concentration increased rapidly during the first trimester (0.5 +/- 0.1 to 14.6 +/- 1.7 ng/ml and 1.0 +/- 0.6 to 21.8 +/- 4.8 ng/ml, in singleton and twin-bearing groups respectively), then progressively between days 160 and 20 prepartum (31.6 +/- 6.2 to 114.3 +/- 31.3 ng/ml and 41.6 +/- 7.4 to 155.8 +/- 36.6 ng/ml in singleton and twin-bearing cows respectively). The mean concentration between days 20 and 10 prepartum approximately tripled (P < 0.001) in both these groups of cows (114.3 +/- 31.1 to 493.0 +/- 75.3 ng/ml and 155.8 +/- 36.6 to 409.3 +/- 114.7 ng/ml in singleton and twin-bearing cows respectively), but between days 10 prepartum and parturition the values increased about threefold (P < 0.01) in the singleton group (493.0 +/- 75.3 to 1352.8 +/- 286.5 ng/ml) and fivefold (P < 0.001) in the twin-bearing group (409.3 +/- 114.7 to 2154.0 +/- 505.7 ng/ml). The two cows in group 3 that gave birth prematurely to a stillborn calf or to a schistosomus reflexus calf exhibited an aberrant bPAG profile. Our results indicate that peripheral bPAG concentrations are correlated to the stage of gestation and fetal number, and that the profile of the peripheral plasma concentrations provides a useful indication of the feto-placental status.
The effect of recombinant human GH replacement therapy on lipoprotein(a) and other lipid parameters in adults with acquired GH deficiency: results of a double-blind and placebo-controlled trial
Authors: Nolte W , Radisch C , Armstrong VW , Hufner M , von zur Muhlen A
Published: January 2005

The effect of GH substitution on serum lipids and lipoproteins, and in particular lipoprotein(a) (Lp(a)), was investigated in 32 adults with postoperative (acquired) GH deficiency as part of a double-blind, placebo-controlled trial. Seventeen men and fifteen women, aged 18-59 years (mean 42 years) from two centres (Hannover and Gottingen) were randomly assigned to two groups. Group P (placebo) received placebo for the first 12 months and recombinant human GH (rhGH) for the following 12 months (open phase). Group V (verum) was treated with rhGH for two consecutive periods of 12 months each. The target dose of rhGH was 2 U/m2 per day, given subcutaneously daily at bedtime. Serum concentrations of Lp(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides were determined at 0, 12 and 24 months. In group V, Lp(a) increased significantly in the first as well as in the second year of treatment (P=0.02, 12 months versus baseline; P=0.016, 24 months versus 12 months). In contrast, Lp(a) levels remained unchanged in group P during the first 12 months (P=0.826 versus baseline), but increased significantly (P=0.002) during the second year, when all patients were administered GH. The increase in Lp(a) after 12 months of rhGH replacement therapy in all 32 patients was significant for Lp(a) baseline concentrations both above and below 20 mg/dl and was independent of the apolipoprotein(a) isoforms. Total and LDL-C decreased significantly after 1 year and triglycerides after 2 years in group V. A significant reduction was also observed in the TC/HDL-C and the LDL-C/HDL-C ratios. Our study shows an unfavorable effect of rhGH replacement therapy on Lp(a) levels, which is, however, counteracted by a favorable effect of rhGH on TC, LDL-C and the TC/LDL-C and LDL-C/HDL-C ratios.
Diabetes insipidus from sarcoidosis confined to the posterior pituitary
Authors: Loh KC , Green A ,   Dillon WP, Fitzgerald PA , Weidner N , Tyrrell JB
Published: January 2005

A young white man with new-onset central diabetes insipidus was discovered to have a posterior pituitary mass on magnetic resonance imaging. No other radiological abnormalities were noted in the anterior pituitary, infundibulum or hypothalamus. No other endocrinopathies were present: laboratory investigations showed normal basal concentrations of anterior pituitary hormones, including prolactin. The patient was suspected to have sarcoidosis affecting the posterior pituitary, because of the discovery of pulmonary sarcoidosis during his diagnostic evaluation. His symptoms of polydipsia and polyuria responded promptly to intranasal administration of 1-desamino-8-D-arginine vasopressin (DDAVP). The patient demonstrated complete regression of the posterior pituitary mass after a course of corticosteroid therapy. However, his diabetes insipidus persisted and he continues to need DDAVP treatment, currently at 12 months of follow-up. The resolution of the neurohypophysial mass was compatible with the diagnosis of pituitary sarcoidosis and this precluded the need for a transsphenoidal biopsy or surgery.
Follistatin-like immunoreactivity in the cytoplasm and nucleus of spermatogenic cells in the rat
Authors: Ogawa K , Hashimoto O , Kurohmaru M , Mizutani T , Sugino H , Hayashi Y
Published: January 2005

Immunohistochemistry using an antiserum raised against the synthetic follistatin peptide (residues 123-134) was used, in the present study, to detect the stage-specific appearance of immunoreactive follistatin in the rat testis. Follistatin immunoreactivity was not found in Sertoli and Leydig cells, while it was clearly detected in spermatogenic cells. Follistatin-like immunoreactivity was detected in the cytoplasm and nucleus of late pachytene spermatocytes. Although the reaction in the cytoplasm disappeared after meiosis, it continued to be intense in the nucleus from pachytene spermatocytes to round spermatids. This finding indicated that follistatin or its closely related peptide produced in late pachytene spermatocytes migrates from the cytoplasm to the nucleus. We subjected rat testis homogenate to affinity chromatography on a sulfate-cellulofine and anti-follistatin Cys (123-134)-Affi-Gel Hz column followed by reverse-phase HPLC and analyzed the resulting fractions by Western blotting using follistatin antiserum. Three major bands at 57, 45 and 39 kDa or four bands at 52, 44, 39 and 34 kDa were detected in crude preparations from rat testis homogenate, under reducing or non-reducing SDS-PAGE respectively. The protein from rat testis, which was recognized by anti-follistatin (123-134) antiserum, exhibited a characteristic pattern for follistatin on SDS-PAGE, i.e. slower migration under reducing conditions than under non-reducing conditions, suggesting that it was follistatin or its closely related protein. Follistatin or its closely related protein may be a stage-specific modulator of spermatogenesis. Since follistatin-like immunoreactivity was not found in oocytes in any stage of development from embryonic to adult rats, it may act in an event specific to spermatogenesis, such as nuclear condensation.
Species differences between male rat and ram pituitary somatostatin receptors involved in the inhibition of growth hormone secretion
Authors: Briard N , Dutour A , Epelbaum J , Sauze N , Slama A , Oliver C
Published: January 2005

The sheep is a valuable model in which to study GH neuroregulation as its pattern of GH secretion is very close to that in humans. Furthermore, important differences in somatostatin (SRIH) action between rats and sheep have been found previously. Our goal was to compare in male rat and ram pituitaries the binding characteristics of somatostatin receptors and the effect of SRIH and 17 analogues on GH release. Using radioautography, SRIH binding was seen to be evenly distributed over the anterior pituitary of both species. In the binding assay, binding sites were three times more concentrated in rats than in sheep. Important interspecies differences in the action of SRIH and its analogues were found: they inhibited GH at lower concentrations in rats than in sheep. Seven peptides displayed greater inhibitory ability in sheep than in rats while three were more potent in rats. Agonistic potencies to inhibit GH release in rats were correlated with somatostatin receptors subtype 2 (sst2) affinities. Our data confirm and extend the quantitative differences between rat and sheep in SRIH inhibitory action on GH secretion and confirm that ligand-binding properties of a given receptor subtype cannot be extrapolated across species.
Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein
Authors: Kanety H , Silbergeld A , Klinger B , Karasik A , Baxter RC , Laron Z
Published: January 2005

A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.
Lack of effects of circulating thyroid hormone levels on serum leptin concentrations
Authors: Corbetta S , Englaro P , Giambona S , Persani L , Blum WF , Beck-Peccoz P
Published: January 2005

Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur.
Bone maturation in girls with Turner's syndrome
Authors: Even L , Bronstein V , Hochberg Z
Published: January 2005

The mechanism of growth retardation in Turner's syndrome has not been resolved. It is often referred to as a bone dysplasia, although endocrine derangement has not been ruled out. The present study was undertaken to evaluate the maturation of individual bones of the hand and wrist in girls with Turner's syndrome and thereby obtain information which may aid in elaborating the possible mechanism of the growth retardation in girls with Turner's syndrome. Hand and wrist films of 24 girls with Turner's syndrome, 11 normal girls with short stature and 23 normal controls were evaluated, using the references of Greulich and Pyle. Each bone or epiphysis was given an individual 'age'. During childhood the Turner patients showed the greatest delay in bone age of the phalangeal bones while the least delayed were the radius and ulna (long bones) and metacarpals. The carpal bones showed intermediate retardation. This pattern and extent of maturational retardation was clearly different from that of the short stature normal group, who showed uniform retardation of all bones. During adolescence, the phalangeal bones were further retarded and the carpal bones showed a moderate retardation. The unique profile of bone maturation in Turner's syndrome suggests an insult to chondroplasia, which may be related to estrogen deficiency or to an as yet undetermined endocrine or paracrine derangement.
Leptin concentrations in serum from a randomly recruited sample of 50- to 80-year-old men and women: positive association with plasma insulin-like growth factors (IGFs) and IGF-binding protein-3 in lean, but not in obese, individuals
Authors: Seck T , Englaro P , Blum WF , Scheidt-Nave C , Rascher W , Ziegler R , Pfeilschifter J
Published: January 2005

OBJECTIVE: The GH/IGF axis is thought to play an important role in the regulation of body composition throughout life. Changes in body fat stores also affect the activity of the GH/IGF axis, but the mechanisms whereby body fat status is signaled to the GH/IGF axis are poorly understood. The newly discovered protein leptin is exclusively produced by adipocytes, and circulating concentrations of leptin closely reflect body fat stores. DESIGN: We here examined whether leptin might be associated with the activity of the GH/IGF axis in a population-based sample. PATIENTS AND METHODS: Circulating concentrations of leptin, IGF-I, IGF-II, and insulin-like growth factor-binding protein-3 (IGFBP-3) were measured in a population-based sample of 50- to 80-year-old men (n=217) and women (n=198) by specific RIA. RESULTS: All three IGF components were significantly positively correlated with leptin in lean women (body mass index (BMI) <25 kg/m2). IGF-II was also positively correlated with leptin in lean men, and positive correlation of leptin with IGF-I in lean men was of borderline statistical significance. In contrast, no correlation was observed in moderately overweight (BMI 25-30kg/m2) and obese individuals (BMI >30 kg/m2). CONCLUSION: Our study shows that serum leptin concentrations are significantly associated with circulating IGF components in lean elderly subjects. The precise mechanism of this interaction between leptin and the GH/IGF system remains to be determined.
Serum leptin and insulin concentrations in patients with insulinoma before and after surgery
Authors: Popovic V , Micic D , Danjanovic S , Zoric S , Djurovic M , Obradovic S , Petakov M , Dieguez C , Casanueva FF
Published: January 2005

Inferential studies suggest that circulating insulin concentrations positively regulate leptin secretion by adipocytes. In humans, however, insulin requires prolonged periods of time, and relatively artificial set-ups before a relationship with leptin can be observed. In the present work, serum leptin concentrations were measured in five patients with insulinoma before and one month after surgery and in five control subjects matched by sex and body mass index (BMI). The control subjects presented a mean serum leptin concentration of 6.7+/-1.5 microg/l and a BMI of 24.9+/-1.1. The mean serum leptin concentration in patients with insulinoma was 11.8+/-3.1 microg/l (P < 0.05 vs controls), with a BMI of 26.3+/-1.9. After surgery, there was a non-significant reduction in BMI (25.8+/-1.7), and a clear reduction in serum leptin concentration (5.6+/-2.4 microg/l, P < 0.05 vs pre surgical values and no difference vs control subjects). The fasting area under the curve (AUC) of insulin concentration (in mU/l per 120 min) before surgery was 14421+/-4981 and after surgery was 1306-/+171 (P < 0.05). Before surgery, serum leptin concentrations significantly correlated with BMI (r = 0.71) and AUC of insulin (r = 0.82), a correlation that was lost after surgery. In conclusion, serum leptin concentrations are significantly elevated in patients with chronically high insulin levels due to insulinoma. After surgical treatment and normalization of insulin values, leptin levels return to normal.
Hyperphagia in children with craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of appetite
Authors: Roth C , Wilken B , Hanefeld F , Schroter W , Leonhardt U
Published: January 2005

Patients with craniopharyngioma frequently suffer from severe obesity. Leptin induces an inhibition of appetite via hypothalamic receptors. This study was undertaken to investigate whether a relationship exists between serum leptin levels and pituitary/hypothalamic lesions in craniopharyngioma patients. Serum leptin levels were evaluated by RIA in 14 patients (age 7-21 years; 7 females, 7 males) after they had undergone neurosurgical treatment for craniopharyngioma. Normal controls had a positive correlation between leptin levels and body mass index (BMI) with higher levels in the females than in the males. Significantly elevated leptin levels with respect to BMI were found in 11 craniopharyngioma patients who had been affected by a suprasellar tumour, whereas 3 patients with an intrasellar tumour had lower, almost normal serum leptin levels. Our data suggest that craniopharyngioma patients develop hypothalamic obesity because their hypothalamic structures are insensitive to endogenous leptin. The elevated serum leptin concentrations found only in patients with a suprasellar tumour may be explained by a disturbed feedback mechanism from the hypothalamic leptin receptors to the adipose tissue.
Effects of thyroid status on insulin-like growth factor-I, growth hormone and insulin are modified by food intake
Authors: Morovat A , Dauncey MJ
Published: January 2005

Understanding the interactions between metabolic signals that regulate insulin-like growth factor-I (IGF-I) is crucial to a recognition of mechanisms that control mammalian growth. Thyroid hormones (THs) are essential for normal growth and development, and it has been suggested previously that they can modify circulating IGF-I concentrations. However, the fact that THs influence food intake, which can itself affect plasma IGF-I levels, has been ignored in previous studies. We have therefore investigated the effects of thyroid status on plasma IGF-I under conditions of controlled food intake in young growing pigs. Circulating IGF-I, growth hormone (GH) and insulin levels, were studied in hypo- and hyperthyroid animals on the same level of food intake as euthyroid controls. In addition, a separate group of hyperthyroid animals was given double the amount of food, in order to assess the influence of increased food intake, as would occur naturally in the hyperthyroid state. Hypothyroid animals and hyperthyroids with extra food had the greatest increase in body weight over the 3 weeks of treatment. These two groups had significantly higher circulating IGF-I and insulin concentrations than either the euthyroid or hyperthyroid animals on the same food intake. Integration of GH concentrations from samples taken every 20 min over a 9 h period showed that, by contrast with IGF-I and insulin levels, GH levels were significantly lower in hypothyroids and hyperthyroids on extra food compared with the euthyroids and the hyperthyroids on the same food intake. We conclude that the effects of thyroid status on IGF-I are mediated in part by the effects that THs have on energy balance, and that nutritional signals are capable of modifying the influence of thyroid status per se on circulating IGF-I concentrations.
Cell-based therapy for insulin-dependent diabetes mellitus
Authors: Efrat S
Published: January 2005

Insulin-secreting pancreatic beta-cell lines represent a promising approach for treatment of insulin-dependent diabetes mellitus. Such cell lines can provide an abundant and reproducible source of beta-cell material for transplantation. A number of highly differentiated beta-cell lines have been developed using transgenic mice. These cells produce insulin amounts comparable to normal pancreatic islets and release it in response to physiological insulin secretagogues. Our laboratory has employed a reversible transformation approach to tightly regulate cell replication in these beta-cell lines, both in culture and in vivo. Beta-cell lines can be modulated by gene transfer to improve their function and survival. We have utilized adenovirus genes, which downregulate antigen presentation and increase cell resistance to cytokines, to facilitate transplantation of mouse beta cells across allogeneic barriers. These approaches could be applied to the development of human beta-cell lines by genetic engineering of isolated human islets.
High serum cholesterol levels in persons with 'high-normal' TSH levels: should one extend the definition of subclinical hypothyroidism?
Authors: Michalopoulou G , Alevizaki M , Piperingos G , Mitsibounas D , Mantzos E , Adamopoulos P , Koutras DA
Published: January 2005

OBJECTIVE: The association between established hypothyroidism and high cholesterol levels is well known. The aim of the present study was to investigate the effect of thyroxine (T4) administration on cholesterol levels in hypercholesterolemic subjects with TSH levels within the normal range ('high-normal' TSH compared with 'low-normal' TSH). DESIGN AND METHODS: We determined TSH levels in 110 consecutive patients referred for hypercholesterolemia (serum cholesterol >7.5 mmol/l). Those with 'high-normal' TSH (2.0-4.0 microU/ml) as well as those with 'low-normal' TSH (0.40-1.99 microU/ml) were randomly assigned to receive either 25 or 50 microg T4 daily for two months. Thus, groups A and B (low-normal TSH) received 25 and 50 microg T4 respectively and groups C and D (high-normal TSH) received 25 and 50 microg T4 respectively. Serum T4, tri-iodothyronine (T3), TSH, free thyroxine index, resin T3 uptake and thyroid autoantibodies (ThAab) as well as total cholesterol, high and low density lipoprotein cholesterol (HDL, LDL), and triglycerides were determined before and at the end of the two-month treatment period. RESULTS: TSH levels were reduced in all groups. The most striking effect was observed in group D (TSH levels before: 2.77+/-0.55, after: 1.41+/-0.85 microU/ml, P < 0.01). Subjects in groups C and D had a higher probability of having positive ThAabs. A significant reduction in total cholesterol (P < 0.01) and LDL (P < 0.01) was observed after treatment only in group D. In those subjects in group D who were ThAab negative, there was no significant effect of thyroxine on cholesterol levels. CONCLUSIONS: Subjects with high-normal TSH levels combined with ThAabs may, in fact, have subclinical hypothyroidism presenting with elevated cholesterol levels. It is possible that these patients might benefit from thyroxine administration.
Cushing's disease: a comparison of pituitary corticotroph microadenomas and macroadenomas
Authors: Selvais P , Donckier J , Buysschaert M , Maiter D
Published: January 2005

Cushing's disease appears as a functionally heterogeneous disease, but criteria that are able to distinguish between different clinical forms remain elusive. We compared two subgroups of patients with proven Cushing's disease according to the size of the pituitary adenoma, evaluated by computed tomography or magnetic resonance imaging. Our series comprised 11 patients with a microadenoma and 10 with a macroadenoma (median volumes (range): 173 (13-270) and 3022 (500-10312) mm3 respectively; P < 0.0001). The clinical presentation was similar in the two groups, but the time elapsed before diagnosis was longer, and visual impairment was less frequent in the patients with a microadenoma (1.5+/-0.8 years and 0%) than in those with a macroadenoma (0.7+/-0.6 years and 40%; P < 0.05). Morning and evening peripheral concentrations of ACTH were greater in patients with macroadenoma (134+/-78 and 130+/-7 ng/l respectively) than in those with microadenoma (52+/-28 and 56+/-19 ng/l, P < 0.05). Hypokalaemia and lymphopenia were also more pronounced in patients with macroadenoma (3.4+/-0.3 mmol/l and 1273+/-401 lymphocytes/mm3) than in those with microadenoma (3.8+/-0.3 mmol/l and 1852+/-668 lymphocytes/mm3 P < 0.05), although morning and evening plasma cortisol concentrations were similar in both groups. In patients with macroadenoma, there was less relative nycthemeral variation of ACTH concentrations (28+/-24%, compared with 62+/-39% in those with microadenoma; P < 0.05), less suppression of plasma cortisol by high doses of dexamethasone (-30+/-14%, compared with -61+/-25%; P < 0.05), and a reduced concentration ratio of mean basal cortisol to ACTH (7+/-3, compared with 12+/-5; P < 0.05). Plasma IGF-I concentration and the TSH peak response to TRH were significantly lower in patients with macroadenoma than in those with microadenoma (0.4+/-0.2 x 10(3) IU/I and 2.3+/-1.8 mIU/I, compared with 1.8+/-0.6 x 10(3) IU/I and 5.2+/-1.6 mUI/l; P < 0.05). Thus, in comparison with microadenomas, corticotroph macroadenomas are characterized by a greater and more autonomous ACTH secretion, inducing more pronounced biological signs of hypercorticism, and are more often accompanied by visual field defects and impairment of other pituitary hormonal secretions.
Megavoltage pituitary irradiation lowers but seldom leads to safe GH levels in acromegaly: a long-term follow-up study
Authors: Thalassinos NC , Tsagarakis S , Ioannides G , Tzavara I , Papavasiliou C
Published: January 2005

Radiotherapy (RT) has long been used in the treatment of acromegaly, but confusion regarding the definition of biochemical cure has hampered interpretation of previous reports on the outcome of this treatment. In the present study we present additional data using the currently accepted criteria of biochemical cure in a large group of patients followed up by our department. Forty-six acromegalic patients were treated with external beam megavoltage RT and followed up for a mean of 7.6 years (range 2-22 years). Only four patients had had previous surgical treatment by either transsphenoidal or transfrontal routes. Following RT, mean basal GH levels decreased from 30.9 ng/ml (5-96 ng/ml) to 11.5 ng/ml (1-36 ng/ml) at 10 years of follow up with a further fall to 6.1 ng/ml (1-29 ng/ml) in those patients followed up for more than 10 years. As a result, although mean GH levels of less than 5 ng/ml were achieved in 9/28 (30.1%) at 5 years, 6/19 (31.6%) at 10 years, and in 6/11 (54.5%) of those patients followed up for more than 10 years post-RT, only 0/28 (0%), 7/28 (25%), 4/19 (21%) and 1/11 (1%) achieved GH levels of <2.5 ng/ml at 2, 5. 10 and >10 years following RT. Thus, in the whole series only 10/48 (20.8%) patients showed a decrease of GH level to less than 2.5 ng/ml at their latest follow up. Hypopituitarism as a result of RT was only infrequently observed in this series; gonadal deficiency developed in 12 (26.6%) patients, thyrotrophin (TSH) deficiency in 3 (6.6%) and adrenocorticotrophin deficiency in 2 (4.4%). In conclusion, megavoltage RT is an effective treatment for the control of GH hypersecretion in acromegaly, with a continuing lowering effect for several years following RT but seldom leads to safe GH levels.
Lead poisoning secondary to hyperthyroidism: report of two cases
Authors: Klein M , Barbe F , Pascal V , Weryha G , Leclere J
Published: January 2005

With long-term exposure to lead, lead accumulates in bone, where it is stored for years. These quiescent lead stores are mobilised when increased bone turnover occurs, and latent lead toxicity may then become symptomatic. Although Graves' disease is a common cause of increased bone turnover, to date hyperthyroidism has been implicated in lead poisoning only twice. We describe herein two cases of hyperthyroidism, one caused by toxic multinodular thyroid enlargement, the second by Graves' disease, leading to lead poisoning. Treatment of hyperthyroidism with radioactive iodine cured both hyperthyroidism and lead poisoning and no chelating agent therapy was necessary. Lead poisoning is an important environmental health problem, and physicians must be aware of the endocrine disorders such as hyperthyroidism and hyperparathyroidism that increase bone turnover, favouring lead mobilisation. Atypical symptoms should draw the physician's attention to the possibility of lead poisoning, particularly in workers with occupational exposure to lead and in areas where lead poisoning is endemic.
Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats
Authors: Katsuki Y , Takano Y , Futamura Y , Shibutani Y , Aoki D , Udagawa Y , Nozawa S
Published: January 2005

OBJECTIVE: Dienogest, a synthetic steroid with progestational activity, is used as a component of oral contraceptives and is currently being evaluated clinically for the treatment of endometriosis. The present study was conducted to confirm the effects of dienogest on experimental endometriosis in rats and to elucidate its mechanism of action. DESIGN: Experimental endometriosis induced by autotransplantation of endometrium in rats. METHODS: Endometrial implants, immune system, and bone mineral were investigated after 3 weeks of medication. RESULTS: Dienogest (0.1-1 mg/kg per day, p.o.) reduced the endometrial implant volume to the same extent as danazol (100 mg/kg per day, p.o.). Simultaneously, dienogest ameliorated the endometrial implant-induced alterations of the immune system: i.e. it increased the natural killer activity of peritoneal fluid cells and splenic cells, decreased the number of peritoneal fluid cells, and decreased interleukin-1beta production by peritoneal macrophages. In contrast, danazol (100 mg/kg per day, p.o.) and buserelin (30 microg/kg per day, s.c.) had none of these immunologic effects. Additionally, combined administration of dienogest (0.1 mg/kg per day) plus buserelin (0.3 microg/kg per day) suppressed the bone mineral loss induced by buserelin alone, with no reduction of the effect on endometrial implants. In vitro studies on dienogest revealed an antiproliferative effect on rat endometrial cells due to inhibition of protein kinase C activity plus a partial progestational effect. CONCLUSIONS: Dienogest appears to be a potent agent with mechanisms of action different from those of danazol and GnRH agonists currently available for the treatment of endometriosis.
Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young
Authors: Velho G , Froguel P
Published: January 2005

Maturity onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date, three MODY genes have been identified on chromosomes 20q (MODY1/hepatic nuclear factor (HNF)-4alpha), 7p (MODY2/glucokinase) and 12q (MODY3/HNF-1alpha). Mutations in MODY2/glucokinase result in mild chronic hyperglycaemia as a result of reduced pancreatic beta-cell responsiveness to glucose, and decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis after meals. In contrast, MODY1 and MODY3 are characterised by severe insulin secretory defects, and by major hyperglycaemia associated with microvascular complications. The role of the three known MODY genes in susceptibility to the more common late-onset NIDDM remain uncertain. Genetic studies seem to exclude a role as major susceptibility genes, but leave unresolved whether they may have a minor role in a polygenic context or an important role in particular populations.
Autoregulation of hepatic glucose production
Authors: Moore MC , Connolly CC , Cherrington AD
Published: January 2005

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.