bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of growth hormone therapy in children with achondroplasia: growth pattern, hypothalamic-pituitary function, and genotype
Authors: Tanaka H , Kubo T , Yamate T , Ono T , Kanzaki S , Seino Y
Published: January 2005

OBJECTIVE: Although there are a few reports on GH therapy in achondroplasia, these were based on a small sample and/or short-term observation. To clarify the effectiveness of GH treatment on short stature in achondroplasia and hypochondroplasia, a long-term treatment study in a larger number of patients was performed. METHOD: Forty-two children (16 males and 26 females, age 3-14 years) with achondroplasia were examined in this study. Initially, we evaluated hypothalamic-pituitary function and point mutation analysis as previously reported. After the evaluation, the children were treated with GH for more than 2 years; then post-treatment growth velocity and body proportion parameters were determined. RESULTS: The 35 typical variants of our achondroplasia patients showed previously reported point mutation in the fibroblast growth factor receptor 3 gene. The annual height gain during GH therapy was significantly greater than that before therapy (3.9 +/- 1.0 cm/year before treatment vs 6.5 +/- 1.8 cm/year for the first year and 4.6 +/- 1.6 cm/year for the second year of treatment). The body disproportion had not been aggravated during the treatment period. CONCLUSION: We conclude that GH might be beneficial in the treatment of short stature in children with achondroplasia in the first 2 years of treatment.
Preserved activation of thyrotropin receptor antibody to stimulate thyroid function despite long-term treatment in euthyroid patients with Graves' disease
Authors: Akuzawa M , Murakami M , Yamada M , Satoh T , Shimizu H , Mori M
Published: January 2005

Clinical evaluation was conducted to ascertain whether thyrotropin receptor antibody (TRAb) in the normal range may still be involved in the regulation of thyroid function after prolonged treatment for Graves' disease. All patients (n = 33) were treated with antithyroid drugs for an average of 10.6 years and were under euthyroid conditions in which normal blood levels of tri-iodothyronine (T3) were significantly correlated with blood thyrotropin (TSH) levels, but not with titers of TRAb. A significant correlation was observed between TRAb titer and thyroid-stimulating antibody (TSAb) activity. In contrast, this correlation was not found in normal subjects. After administration of T3 (75 microg daily for 8 days), the patients showed increased levels of T3 with concomitant suppression of TSH levels. Under these conditions, linear regression analysis showed significant correlations of TRAb titer and TSAb activity with 24-h thyroid radioiodine uptake (r = 0.641 and 0.621 respectively, P < 0.01), in contrast to declining blood thyroxine levels. Moreover, the immunoglobulin G (IgG) of the patients precipitated to a greater extent than IgG from normal subjects a peptide consisting of the amino acid sequence near the terminus of the human TSH receptor. These findings indicated that TRAb at normal levels possessed significant unremitting activities on thyroid function despite long-term treatment in euthyroid patients with Graves' disease.
Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro
Authors: van Wijk PA , Rijnberk A , Croughs RJ , Meij BP , Mol JA
Published: January 2005

Extrinsic factors such as hypothalamic hormones or intrapituitary growth factors may stimulate clonal expansion of a genomically altered cell and therefore play a role in pituitary tumorigenesis. Here we report on the effects of the hypophysiotrophic hormones corticotrophin-releasing hormone (CRH) and vasopressin (AVP) and the intrapituitary growth factor insulin-like growth factor-I (IGF-I) on the proliferation of, as measured by the bromodeoxyuridine labelling index, and ACTH secretion by normal canine pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism. The sensitivity to inhibition by cortisol was analysed under various conditions. Under basal conditions, no significant differences were found in the bromodeoxyuridine labelling indices between control cells and tumour cells. CRH, AVP, IGF-I and cortisol had no effect on the proliferation of canine pituitary cells or canine corticotrophic adenoma cells. In contrast with normal pituitary cells, the proliferation of corticotrophic adenoma cells was stimulated by fetal calf serum (FCS). This FCS-induced proliferation was not inhibited by cortisol. The CRH-induced ACTH secretion by corticotrophic adenoma cells was significantly (P < 0.05) lower than that by normal pituitary cells after 4 h incubation with CRH. Incubation with cortisol for 24 h resulted in reduced ACTH secretion under basal and AVP- or IGF-I-stimulated conditions. The relative inhibition was, however, significantly (P < 0.05) lower in ACTH-producing tumour cells than in normal pituitary cells. Cortisol did not inhibit the CRH-induced ACTH secretion in normal pituitary cells after 24 h. In conclusion, canine corticotrophic adenomas are less sensitive to stimulation by CRH and less sensitive to inhibition by glucocorticoids. These tumours have an aberrant sensitivity to a growth-promoting factor present in FCS. This factor may have an important role in the growth promotion of canine corticotrophic tumours.
Aging is associated with changes in allopregnanolone concentrations in brain, endocrine glands and serum in male rats
Authors: Bernardi F , Salvestroni C , Casarosa E , Nappi RE , Lanzone A , Luisi S , Purdy RH , Petraglia F , Genazzani AR
Published: January 2005

OBJECTIVE: Allopregnanolone is a potent neuroactive steroid hormone produced in the brain and in peripheral endocrine glands. The present study investigated possible age-related variations in allopregnanolone content in brain areas, endocrine glands and serum of male rats. DESIGN: Wistar male rats were categorized into 5 groups (6 rats in each) according to age: 6, 12, 16, 18 and 20 months respectively. METHODS: Allopregnanolone content in acidic homogenates of brain cortex, hypothalamus, pituitary, adrenals and gonads was measured by a specific radioimmunoassay. Serum allopregnanolone, corticosterone and testosterone were also assayed by radioimmunoassay. RESULTS: Brain cortex allopregnanolone content decreased significantly with age, while hypothalamic allopregnanolone content remained constant until 18 months and increased significantly at 20 months. Pituitary content showed a significant age-related reduction. Adrenal allopregnanolone content remained constant until 18 months, and was significantly higher at 20 months. Testis and serum allopregnanolone contents showed significant age-related increases. Serum testosterone levels showed an age-related decrease, while no age-related variation in serum corticosterone was found. CONCLUSIONS: The present study showed a significant impact of aging on allopregnanolone contents in brain, endocrine glands and serum, showing an age-related decrease in brain cortex and pituitary, and an age-related increase in testes, adrenals and serum.
Changes in carbohydrate metabolism of testicular germ cells during meiosis in the rat
Authors: Bajpai M , Gupta G , Setty BS
Published: January 2005

A study was undertaken to estimate the activities of the key enzymes of glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle in purified rat spermatocytes and spermatids, which have been shown to die in glucose-containing medium and require lactate/pyruvate for maintaining normal ATP concentrations. The aim was to elucidate the changes in the glycolytic and oxidative potential of germ cells undergoing meiosis. Pachytene spermatocytes and round spermatids from adult rat testis were purified to approximately 90% purity by trypsin digestion followed by a combination of centrifugal elutriation and Percoll density gradient centrifugation. After the purity and viability of these cells had been established, their contents of hexokinase, phosphofructokinase, lactate dehydrogenase (LDH) and LDH-X of glycolysis, glucose 6-phosphate dehydrogenase of the pentose phosphate pathway and citrate synthase, aconitase, malate dehydrogenase and 2-oxoglutarate dehydrogenase of the TCA cycle were estimated. These enzymes were also estimated in epididymal spermatozoa for comparison with the testicular germ cells. The results indicate greater activity of glycolytic and pentose phosphate pathway enzymes in spermatocytes than in spermatids, which exhibited greater activity of TCA cycle enzymes than the former. The difference in activity was statistically significant for most of the enzymes studied. In contrast, spermatozoa exhibited markedly greater activity of glycolytic enzymes and significantly lower activity of pentose phosphate pathway and TCA cycle enzymes than did the testicular germ cells. We conclude that the unusual dependence of spermatids exclusively on lactate may be due to their lower glycolytic potential, whereas spermatocytes with comparatively greater glycolytic activity have an intermediate dependence on lactate and are therefore able to utilise lactate, pyruvate, or both, while retaining a better ability to utilise glucose. Spermatozoa with the greatest glycolytic potential and the lowest TCA cycle activity appear to be 'programmed' to utilise exclusively glucose/fructose for energy.
Inhibition by gonadotropins of interleukin-1 production by rabbit granulosa and theca cells: effects on gonadotropin-induced progesterone production
Authors: Breard E , Delarue B , Benhaim A , Feral C , Leymarie P
Published: January 2005

Increasing evidence suggests that cytokines may play a role in ovarian processes. The purpose of this study was to determine if interleukin-1 (IL-1) could modulate rabbit pre-ovulatory follicular function and to explore cellular sites of IL-1 biosynthesis in rabbit follicles. Development of rabbit pre-ovulatory follicles was induced by 200 mIU equine chorionic gonadotropin daily for 2 days. Seventy-two hours after the last injection, ovaries were excised and granulosa and theca cells isolated. The two types of cell were pre-incubated for 24 h in Minimum Essential Medium (MEM) with 5% fetal calf serum (FCS), and then incubated for 24 h in MEM with 2.5% FCS with appropriate stimulants. Results showed that rabbit granulosa and theca cell culture supernatants contain IL-1 bioactivity and that this bioactivity was diminished by gonadotropins, FSH and human chorionic gonadotropin, in a dose-dependent manner. Low doses of IL-1 (1 ng/ml) inhibited gonadotropin-induced progesterone production in both cell types and at the same time increased cell numbers. A study of the mechanism of IL-1 action demonstrated that it affects cAMP generation, and also steps distal to cAMP formation. We conclude that in our model gonadotropins, by inhibiting IL-1 production, could control IL-1 modulation of gonadotropin action on steroidogenesis.
Bradykinin potentiates insulin-stimulated glucose uptake and enhances insulin signal through the bradykinin B2 receptor in dog skeletal muscle and rat L6 myoblasts
Authors: Miyata T , Taguchi T , Uehara M , Isami S , Kishikawa H , Kaneko K , Araki E , Shichiri M
Published: January 2005

Previously we demonstrated that bradykinin infusion could increase glucose uptake into dog peripheral tissues, and that bradykinin could potentiate insulin-induced glucose uptake through glucose transporter 4 (GLUT4) translocation in dog adipocytes. However, skeletal muscle is the predominant tissue for insulin-mediated glucose disposal. The aim of this study was to determine how bradykinin affected insulin-stimulated glucose uptake in dog skeletal muscle and myotubes transformed from rat L6 myoblasts. The bradykinin receptor binding studies revealed that dog skeletal muscle and rat L6 myoblasts possessed significant numbers of bradykinin receptors (Kd = 88 and 76 pmol/l, Bmax = 82.5 and 20 fmol/mg protein respectively). An RT-PCR (reverse transcriptase-polymerase chain reaction) amplification showed mRNA specific for bradykinin B2 receptor in both cells. Bradykinin significantly increased 2-deoxyglucose uptake in isolated muscle and L6 myoblasts in the presence of insulin (10(-7) mol/l) in a dose-dependent manner, but not in the absence of insulin. Bradykinin also enhanced insulin-stimulated GLUT4 translocation, and insulin-induced phosphorylation of insulin receptor beta subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in both cells. It is concluded that bradykinin could potentiate the insulin-induced glucose uptake through GLUT4 translocation in dog skeletal muscle and rat L6 myoblasts. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by an increase in GLUT4 translocation.
Expression of mRNA coding for four catecholamine-synthesizing enzymes in human adrenal pheochromocytomas
Authors: Isobe K , Nakai T , Yukimasa N , Nanmoku T , Takekoshi K , Nomura F
Published: January 2005

OBJECTIVE: To understand the molecular mechanisms by which catecholamine synthesis is controlled in pheochromocytomas--tumors that synthesize and release catecholamines, which are related to various clinical manifestations of the condition. METHODS: We measured the concentrations of mRNA coding for the catecholamine-synthesizing enzymes tyrosine hydroxylase, aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyl transferase (PNMT) and for the catecholamine contents in 12 pheochromocytomas and 12 normal adrenal medullas. RESULTS: The mean content of total catecholamine and the beta-actin mRNA expression in the pheochromocytomas were almost the same as those in the normal adrenal medullas. However, the tyrosine hydroxylase, AADC and DBH mRNA concentrations in the pheochromocytomas were greater than those of the normal adrenal medullas. Conversely, the PNMT mRNA concentration in the pheochromocytomas was lower than that in the normal adrenal medullas. These differences are responsible for the difference in the proportions of catecholamines between pheochromocytomas and normal adrenal medullas. The constitutive expression of the catecholamine-synthesizing enzyme mRNAs varied in magnitude among the pheochromocytomas, and the tyrosine hydroxylase mRNA expressions correlated with the contents of total catecholamine in the tumors (r=0.964, P<0.0001). CONCLUSIONS: These findings indicate that catecholamine production in pheochromocytomas is primarily controlled by the level of gene expression.
Increased plasma concentration of epidermal growth factor in female patients with non-toxic nodular goitre
Authors: Brzezinski J , Lewinski A
Published: January 2005

OBJECTIVE: Epidermal growth factor (EGF) is believed to be one of the most potent growth factors for the thyroid gland. DESIGN AND METHODS: We tested plasma EGF concentrations (radioreceptor method) in patients with non-toxic nodular goitre (NNG). Blood samples from patients with NNG were collected on the day before the surgery, during subtotal thyroidectomy (sTx)--from peripheral and thyroid veins, on the 3rd day after sTx, 3 months after sTx, and 9 months after the surgery. RESULTS: Before the operation, the mean plasma EGF concentration in 50 women with NNG was significantly higher (1.16 +/- 0.69 ng/ml; mean +/- S.E.) than that in 32 control female patients subjected subsequently to other (non-thyroid) operations (0.41 +/- 0.27 ng/ml; P < 0.001), and that in 20 healthy women (0.35 +/- 0.11 ng/ml; P < 0.001), both of which groups were without goitre or had a small non-toxic diffuse goitre. The surgical treatment of NNG resulted in a significant reduction in plasma EGF 3 months after sTx (0.56 +/- 0.22 ng/ml). A further slight decrease was observed 9 months after sTx (0.44 +/- 0.14 ng/ml). CONCLUSIONS: Our observations confirm the assumption that EGF may participate in the process of goitre formation in human subjects. However, the source of EGF involved in this process remains unclear. Some findings could suggest that plasma EGF, which was increased in patients with NNG, may be of non-thyroid origin; however, the majority of our observations strongly stress the significance of an intact thyroid in the preservation of an unchanged EGF value, suggesting a role of locally produced EGF in the pathogenesis of NNG.
GH response to provocation and circulating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and clinical response to GH therapy in children with beta-thalassaemia
Authors: Soliman AT , El Banna N , Ansari BM
Published: January 2005

The causes of growth retardation of children with thalassaemia major are multifactorial. We studied the GH response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, IGF-I, IGF-binding protein-3 (IGFBP-3) and ferritin, and evaluated IGF-I generation after a single dose of GH (0.1 mg/kg per dose) in 15 prepubertal patients with thalassaemia, 15 age-matched children with constitutional short stature (CSS) (height standard deviation score less than -2, with normal GH response to provocation) and 11 children with isolated GH deficiency (GHD). Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (6.2 +/- 2.3 and 6.8 +/- 2.1 microg/l respectively) than the CSS group (18.6 +/- 2.7 and 16.7 +/- 3.7 microg/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP-3 (47.5 +/- 19 ng/ml and 1.2 +/- 0.27 mg/l respectively) compared with those with CSS (153 +/- 42 ng/ml and 2.06 +/- 0.37 mg/l respectively), but the IGF-I and IGFBP-3 concentrations were not different from those with GHD (56 +/- 25 ng/ml and 1.1 +/- 0.32 mg/l respectively). These data demonstrate that the GH-IGF-I-IGFBP-3 axis in thalassaemic children is defective. Serum ferritin concentration correlated significantly with GH peak response to provocation (r = -0.36, P < 0.05) and circulating IGF-I (r = -0.47, P < 0.01) and IGFBP-3 (r = -0.42, P < 0.01) concentrations. In the IGF-I generation test, after GH injection, the thalassaemic children had significantly lower IGF-I and IGFBP-3 levels 86.7 +/- 11.2 ng/ml and 2.05 +/- 0.51 mg/l respectively) than those in the CSS group (226 +/- 45.4 ng/ml and 2.8 +/- 0.43 mg/l respectively). The IGF-I response was significantly higher in children with GHD (158 +/- 50 ng/ml) than in thalassaemic children. Six short (height standard deviation score less than -2) thalassaemic children who had defective GH response to provocation (< 10 microg/l), all the children with GHD and eight short normal children (CSS) were treated for 1 year with human GH (18 units/m2 per week divided into daily s.c. doses). After 1 year of GH therapy there was a marked acceleration of growth velocity in both thalassaemic children (from 3.8 +/- 0.6 cm/year to 7.2 +/- 0.8 cm/year) and controls. However, the linear acceleration of growth velocity on GH therapy was significantly slower in thalassaemic children (3.3 +/- 0.3 cm/year increment) compared with those with CSS (5.3 +/- 0.4 cm/year increment) and GHD (6.9 +/- 1.2 cm/year increment) (P < 0.05). Their circulating IGF-I concentration (105 +/- 36 ng/ml) was significantly lower than those for CSS (246 +/- 58 ng/ml) and GHD (189 +/- 52 ng/ml) after 1 year of GH therapy. These data prove that some children with beta-thalassaemia major have a defective GH-IGF-I-IGFBP-3 axis and suggest the presence of partial resistance to GH.
GH dependence and GH withdrawal syndrome in GH treatment of short normal children: evidence from growth and cardiac output
Authors: Lampit M , Lorber A , Vilkas DL , Nave T , Hochberg Z
Published: January 2005

The child's age is a significant determinant of the outcome of GH therapy; prepubertal children respond better on both short term and long term growth, whereas adolescents tend to accelerate their bone maturation more than growth. The present study was designed to evaluate the efficacy of an interrupted GH therapy protocol of young, short normal children. GH was given for a period of 3 years, or until they reached the 25th percentile, then discontinued at a young age (not more than 9 years), and then the children's growth followed until final height. Yet, after discontinuation of GH therapy, growth came close to a complete stand-still. The present report focuses on describing the period beyond GH withdrawal and its impact on growth and cardiac performance. Twenty-two children received daily s.c. injections of 0.9 mg/m2 hGH and 12 children were the control, untreated group. Growth and echocardiography were followed during therapy and 2 years thereafter. During GH treatment growth velocity accelerated markedly over the first year; it slowed down over the second and third years, and decelerated after GH withdrawal to a velocity that was significantly lower than pretreatment values. Growth rate remained low for the next year, and recovered to pretreatment velocity by the fourth semiannual measurement. To evaluate the role of the GH-IGF-I axis during the growth deceleration, serum IGF-I, insulin-like growth factor-binding protein-3 (IGFBP-3), and an arginine stimulation test were performed at 1, 3 or 6 months after GH withdrawal, and compared with pretreatment response. GH response was 70% of pretreatment values by 1 month and recovered completely by 3 months post treatment. Serum IGF-I and IGFBP-3 levels were normal throughout. End-systolic and end-diastolic left ventricular dimensions as well as cardiac output did not change during the 2 year course of GH therapy, but fell significantly during the initial 6 months of GH withdrawal. Thus, daily injections of GH to prepubertal short normal children is associated with development of drug dependence, followed during the abstinence period by deceleration of growth and reduction of cardiac output to levels that are lower than pretreatment values. After GH therapy for 30-36 months the withdrawal syndrome persists for 18 months, and is not induced by alterations of serum levels of GH or IGF-I.
Effects of growth hormone treatment on the leptin system and on energy expenditure in abdominally obese men
Authors: Karlsson C , Stenlof K , Johannsson G , Marin P , Bjorntorp P , Bengtsson BA , Carlsson B , Carlsson LM , Sjostrom L
Published: January 2005

The present study has examined the short- and long-term effects of growth hormone (GH) treatment on the leptin system and energy expenditure. Thirty male individuals with abdominal obesity were randomised to GH or placebo treatment in a 9-month, double-blind study. The dose of GH was 9.5 microg/kg, administered subcutaneously every evening. Serum leptin concentrations were measured by a human leptin RIA. Total RNA was isolated from adipose tissue biopsies and leptin mRNA levels were determined by a semi-quantitative reverse transcriptase-PCR assay. Body composition was determined by potassium-40 and the basal metabolic rate (BMR) was measured by a computerised, ventilated, open-hood system. As compared with placebo, an overall decrease in serum leptin concentrations as assessed by the area under the curve (AUC) (P < 0.05) and an increase in BMR (AUC, P < 0.05) were observed during GH treatment. The overall GH-induced changes were due to marked changes in serum leptin concentrations and BMR after 6 weeks of treatment. After 9 months of GH treatment there was a significant reduction in body fat (BF) while serum leptin concentrations and BMR did not differ from baseline values. Leptin mRNA levels did not change over the study period. We speculate that long-term GH treatment induces a new energy balance steady state with decreased BF stores. The effects of GH on the leptin system is suggested to be of importance for the maintenance of a lower BF mass.
Hypoleptinemia in patients with anorexia nervosa: loss of circadian rhythm and unresponsiveness to short-term refeeding
Authors: Balligand JL , Brichard SM , Brichard V , Desager JP , Lambert M
Published: January 2005

Leptin is a protein encoded by the ob gene that is expressed in adipocytes and regulates eating behavior via neuroendocrine mechanisms. Plasma leptin levels have been shown to correlate with weight and body fat in normal, obese and anorexic subjects. In the last of these populations, the dynamic profile of plasma leptin levels during short-term refeeding has never been assessed. We thus investigated basal plasma leptin levels in 29 female patients with anorexia nervosa (AN) (age 21.9 +/- 1.4 years, body mass index (BMI) 15.2 +/- 0.3 kg/m2) and in 80 normal female controls (age 21.2 +/- 0.2 years, BMI 20.3 +/- 0.3 kg/m2, mean +/- S.E.M.). Basal plasma leptin levels in AN were decreased by 77% compared with controls (2.5 +/- 0.2 vs 11.1 +/- 0.7 ng/ml, P < 0.0001). In both AN subjects and controls, plasma leptin levels correlated significantly with BMI (r2 = 0.448, P < 0.0001 and r2 = 0.339, P < 0.0001 respectively). Five AN patients (four female, one male, age 22.0 +/- 4.7 years, BMI 14.2 +/- 0.4 kg/m2, body fat 4.3 +/- 0.9 kg or 11.0 +/- 1.9% of body weight, basal metabolic rate (BMR) 958 +/- 122 kcal/day) were studied during a 3-day refeeding period and compared with eight control subjects (two male, six female, age 25.7 +/- 1.2 years, BMI 21.3 +/- 0.8 kg/m2, body fat 15.1 +/- 0.9 kg or 24.6 +/- 1.7%, BMR 1455 +/- 78 kcal/day) submitted to 36-h fasting. The amount of calories administered was based on BMR + 20% (carbohydrate 60%, protein 17%, fat 23%). In contrast to the rise in leptin levels that occurred during refeeding after a prolonged fast period in normal subjects, plasma leptin levels remained low and unchanged throughout the 3 days of renutrition in AN patients. The circadian rhythm of leptin was also completely abolished. This contrasted with the preserved circadian variations of cortisol, whose mean levels were increased. In conclusion, we confirmed that plasma leptin levels are low in AN and correlate with body weight. We further demonstrated that plasma leptin levels do not respond to short-term refeeding in anorexic patients in whom circadian variations are not restored, which suggests that the acute regulation of leptin by positive changes in energy balance is not preserved under a critical threshold of body fat.
Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal women
Authors: De Leo V , la Marca A , Talluri B , D'Antona D , Morgante G
Published: January 2005

The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA axis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production.
Evidence for modulation of osteocalcin containing gamma-carboxyglutamic acid residues synthesis by insulin-like growth factor-I and vitamin K2 in human osteosarcoma cell line MG-63
Authors: Kudo Y , Iwashita M , Takeda Y , Muraki T
Published: January 2005

The effect of insulin-like growth factor-I (IGF-I) and 2-methyl-3-all-trans-tetraphenyl-1,4-naphtoquinone (vitamin K2) on the synthesis of osteocalcin containing gamma-carboxyglutamic acid (Gla) residues which is the physiologically relevant form in bone metabolism was studied in cultured human osteoblast-like (MG-63) cells. Both IGF-I and vitamin K2 stimulated 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced osteocalcin containing Gla secretion in a concentration-dependent manner. This stimulatory effect of IGF-I and vitamin K2 was additive. Vitamin K2-enhanced osteocalcin containing Gla secretion was selectively suppressed by 3-(alpha-acetonyl-benzyl)-4-hydroxy-coumarin (warfarin). The stimulatory effect of IGF-I was completely abolished by the presence of cycloheximide; in contrast the effect of vitamin K2 was still observed in the presence of cycloheximide. Treatment of MG-63 cells with IGF-I caused an approximately 2.2-fold increase in osteocalcin mRNA levels (determined by reverse transcription-polymerase chain reaction). Vitamin K2 had no effect on either the stimulation of mRNA level by IGF-I or the basal level. IGF-I-stimulated osteocalcin containing Gla secretion was inhibited by one of its binding proteins (insulin-like growth factor binding protein-4) in a concentration-dependent manner. These findings suggest that the modes of action of IGF-I and vitamin K2 on 1.25(OH)2D3-induced osteocalcin containing Gla secretion in MG-63 cells are different.
Cross-linked growth hormone dimers have enhanced biological activity
Authors: Mockridge JW , Aston R , Morrell DJ , Holder AT
Published: January 2005

In this study we have investigated the effect on the bioactivity of pituitary-derived human growth hormone (hGH) and recombinant bovine (b) GH after the addition of various concentrations of the water soluble cross-linking agent 1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC; 6.25-100 mg/ml). The biological activity of resulting cross-linked reactions were determined by its ability to promote incorporation of 35SO4(2-) into costal cartilage of hypopituitary Snell dwarf mice in vivo. Administration of EDC-treated hGH solutions resulted in a significant enhancement of hormone activity in vivo compared with non-cross-linked samples. A similar significant enhancement of bGH activity in vivo was also observed when solutions containing recombinant bGH were cross-linked using EDC. For both hGH and bGH the degree of enhancement appears to be dose-dependent for the concentration of EDC (6.25-100 mg/ml for hGH; 6.25-50 mg/ml for bGH) present in the cross-linking reactions. SDS-PAGE analysis of EDC cross-linked solutions containing hGH and bGH spiked with 125I-hGH and 125I-bGH respectively revealed that dimeric GH was the primary cross-linked component. Increasing the concentration of EDC in cross-linking reactions resulted in increased formation of dimeric hGH and bGH. There was a significant correlation between the amount of GH dimer present and the increase in biological activity, suggesting that GH dimers were responsible for the enhanced biological activity. This was confirmed by the enhanced biological activity of a purified preparation of EDC cross-linked dimeric hGH. In conclusion, covalently cross-linked GH dimers reported here have enhanced bioactivity in vivo. However, since naturally occurring GH dimers are known to have reduced biological activity, this work suggests that the structure of EDC cross-linked GH dimers differs fundamentally from that of native dimeric hGH.
Effects of N-methyl-D-aspartic acid and kainic acid on prolactin secretion in hyper- and hypoprolactinaemic conditions
Authors: Pinilla L , Tena-Sempere M , Aguilar R , Aguilar E
Published: January 2005

OBJECTIVE: The stimulatory and inhibitory effects of N-methyl-D-aspartic acid (NMDA) and kainic acid on prolactin (PRL) secretion have been correlated with the serum prolactin concentrations before drug administration. In the present experiments, we analysed the role of NMDA and kainic acid in PRL secretion in females with different serum concentrations of PRL. METHODS: Hypoprolactinaemic females were obtained by ovariectomy or after administration of diethyldithiocarbamate (an inhibitor of dopamine-beta-hydroxylase). Chronic hyperprolactinaemia was induced by neonatal administration of testosterone or oestradiol and acute hyperprolactinaemia was induced either by administration of alpha-methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) or by ether exposure. To analyse the role of dopamine in the effects of NMDA, we measured pituitary concentrations of dopamine after NMDA treatment and the effects of pretreatment with domperidone. RESULTS: (1) NMDA, but not kainic acid, stimulated PRL release in cyclic females. This effect was independent of serum PRL concentrations and was not accompanied by a decrease in pituitary concentrations of dopamine. (2) NMDA did not change PRL secretion in neonatally androgenized females, whereas NMDA and kainic acid inhibited PRL release in neonatally oestrogenized females. The inhibitory effects of NMDA and kainic acid were blocked by domperidone. (3) Kainic acid inhibited PRL secretion in prepubertal hyper- and hypoprolactinaemic rats. (4) Hyperprolactinaemia induced by ether stress was counteracted by administration of NMDA and kainic acid. CONCLUSIONS: (a) NMDA has a dual effect on prolactin secretion that is independent of prior prolactin concentrations and of dopamine activity, but kainic acid is only inhibitory. (b) The stimulatory or inhibitory effects of NMDA and kainic acid on PRL secretion were not strictly related to basal PRL concentrations and necessarily involved a change in the secretion of prolactin releasing factors, as no correlations were observed between changes in pituitary concentrations of dopamine and serum PRL concentrations. (c) Females rendered hyperprolactinaemic by neonatal administration of testosterone or oestradiol responded differently after NMDA administration. (d) NMDA and kainic acid blocked the mechanisms involved in stress-induced PRL secretion.
Mutations of follicle-stimulating hormone and its receptor: effects on gonadal function
Authors: Huhtaniemi IT , Aittomaki K
Published: January 2005

The physiological functions of the two gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are quite well known in both males and females. Nevertheless, the recent unraveling of structures of the gonadotropin and gonadotropin receptor genes has provided us with tools to obtain completely new information on the functions of these hormones at the molecular level. Several gain- and loss-of-function mutations of these genes have been discovered in humans, and the first knock-out experiments with these genes in the mouse have been recently published. The purpose of the present review is to describe the current state of knowledge on human mutations of FSH and its receptor, as well as on relevant animal models.
Hormonal control of programmed cell death/apoptosis
Authors: Kiess W , Gallaher B
Published: January 2005

Apoptosis or programmed cell death is a physiological form of cell death that occurs in embryonic development and during involution of organs. It is characterized by distinct biochemical and morphological changes such as DNA fragmentation, plasma membrane blebbing and cell volume shrinkage. Many hormones, cytokines and growth factors are known to act as general and/or tissue-specific survival factors preventing the onset of apoptosis. In addition, many hormones and growth factors are also capable of inducing or facilitating programmed cell death under physiological or pathological conditions, or both. Steroid hormones are potent regulators of apoptosis in steroid-dependent cell types and tissues such as the mammary gland, the prostate, the ovary and the testis. Growth factors such as epidermal growth factor, nerve growth factor, platelet-derived growth factor (PDGF) and insulin-like growth factor-I act as survival factors and inhibit apoptosis in a number of cell types such as haematopoietic cells, preovulatory follicles, the mammary gland, phaeochromocytoma cells and neurones. Conversely, apoptosis modulates the functioning and the functional integrity of many endocrine glands and of many cells that are capable of synthesizing and secreting hormones. In addition, exaggeration of the primarily natural process of apoptosis has a key role in the pathogenesis of diseases involving endocrine tissues. Most importantly, in autoimmune diseases such as autoimmune thyroid disease and type 1 diabetes mellitus, new data suggest that the immune system itself may not carry the final act of organ injury: rather, the target cells (i.e. thyrocytes and beta cells of the islets) commit suicide through apoptosis. The understanding of how hormones influence programmed cell death and, conversely, of how apoptosis affects endocrine glands, is central to further design strategies to prevent and treat diseases that affect endocrine tissues. This short review summarizes the available evidence showing where and how hormones control apoptosis and where and how programmed cell death exerts modulating effects upon hormonally active tissues.
Serum leptin levels in children and adolescents with insulin-dependent diabetes mellitus in relation to metabolic control and body mass index
Authors: Kiess W , Anil M , Blum WF , Englaro P , Juul A , Attanasio A , Dotsch J , Rascher W
Published: January 2005

The ob protein, termed leptin, is produced by adipocytes and is thought to act as an afferent satiety signal regulating weight through suppressing appetite and stimulating energy expenditure in humans and/or rodents. Insulin has been found to be a potent stimulator of leptin expression in rodents. It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0.26-14.4ng/ml) and compared with insulin-treated children and adolescents (mean 5.18+/-5.48 ng/ml, range 0.26-29.77 ng/ml) (P<0.0001) even after adjustment for gender and body mass index (BMI). Serum leptin levels in patients with IDDM were significantly correlated with BMI (r=0.42, P<0.0001). Multiple regression analysis showed that age and BMI were significantly correlated with leptin levels, while duration of diabetes, mean HbA1c levels, insulin dose and plasma glucose, triglyceride and cholesterol levels were not. Females had higher serum leptin concentrations than males even when adjusted for BMI (P<0.0001). Surprisingly and most importantly, leptin levels in insulin-treated young adult (Tanner stage 5) patients were significantly higher than values found in the healthy nondiabetic reference population when adjusted for sex, Tanner stage and BMI. These findings suggest that leptin levels in IDDM patients show a similar dependency on adipose tissue and age as in healthy, normal children. The data provide evidence that insulin may be of importance as a regulator of serum leptin levels in vivo not only in rodents but also in humans. It is hypothesized that the elevated BMI-adjusted leptin levels in adolescents with IDDM could indicate either that these patients may be oversubstituted by the intensified insulin therapy that they are receiving or that their body composition and body fat content may differ from that of healthy adolescents in the sense that they have a relative increase in fat mass.
Relationship of chronic endurance exercise to the somatotropic and sex hormone status of older men
Authors: Cooper CS , Taaffe DR , Guido D , Packer E , Holloway L , Marcus R
Published: January 2005

To investigate putative abrogating effects of habitual endurance exercise on age-related changes in endocrine function and body composition, we compared insulin-like growth factor-I (IGF-I), sex hormonal status and body composition in 15 Masters runners and 15 minimally exercising men (MEM) aged 60-70 years. A higher maximal oxygen uptake (VO2 max.) in the runners (41.4+/-1.6 compared with 27.3+/-1.4 ml/kg/min, P=0.0001; mean+/-S.E.M.) reflected our group allocations. Analysis of body composition and bone mineral density (BMD) by dual energy X-ray absorptiometry showed no group differences in lean tissue mass or in regional or whole body BMD, but MEM were heavier, reflecting greater adiposity. Of nine muscle groups tested, only quadriceps strength differed significantly, being greater in runners (60.3+/-2.8 compared with 51.1+/-2.3 kg, P=0.02). Total IGF-I (129+/-10 compared with 124+/-11 ng/ml, P=0.72) and IGF-binding protein-3 (2854+/-94 compared with 2623+/-128ng/ml, P=0.16), were similarly depressed compared with young adult norms in both groups. There was no relationship between total or bioavailable IGF-I and any body composition, BMD or muscle strength variable. In the runners, concentrations of total testosterone (19.1+/-0.8 compared with 15.0+/-0.9 nmol/l, P=0.002) and sex hormone binding globulin (SHBG) (124.4+/-21.6 compared with 67.7+/-11.6 nmol/l, P=0.03) were significantly greater, but the free androgen index was significantly lower (20.7+/-2.7 compared with 31.4+/-4.1, P=0.04). Directly measured free testosterone, however, was similar between the runners and MEM (47.9+/-1.8 compared with 47.1+/-2.0 nmol/l P=0.80). Therefore the group differences in total testosterone and free androgen index were due to their different SHBG concentrations. Although estrone concentration was higher in MEM (85.1+/-5.2 compared with 108+/-6.7 pmol/l, P=0.03), estradiol concentration was similar between groups (73.0+/-6.3 compared with 81.8+/-8.0 pmol/l, P=0.18), indicating that estrogens were not responsible for the increased SHBG in runners. These results indicate that even high levels of regular endurance exercise do not prevent the decline in the somatotropic axis that occurs with aging. Furthermore, the somatic effects of exercise in older men (reduced adiposity and increased regional muscle strength) occurred independently of somatotropic or androgen status. Although habitual exercise does not influence free testosterone concentrations in older men, it appears to enhance the age-associated increase in SHBG synthesis.
IGF-I and IGF-binding protein-1 are related to cortisol in human cord blood
Authors: Cianfarani S , Germani D , Rossi L , Argiro G , Boemi S , Lemon M , Holly JM , Branca F
Published: January 2005

OBJECTIVE: To assess cortisol concentrations in cord blood and investigate their relationships with the IGF system. STUDY DESIGN: Fifteen newborns with birth weight appropriate for gestational age (AGA) and 30 children with intrauterine growth retardation (IUGR) were studied. Serum samples were collected from umbilical cord blood and cortisol, IGF-I and IGF-binding proteins (IGFBPs)-1 and -3 were measured. IUGR infants were followed up for 3 months with repeated measurements of weight, supine length and knee-heel length (by knemometry). RESULTS: IUGR newborns showed significantly greater concentrations of IGFBP-1 (P<0.0001) and lower concentrations of IGF-I (P< 0.0001) and IGFBP-3 (P< 0.0001) than did controls. In AGA children, cortisol correlated inversely with IGF-I (r=-0.75, P< 0.002) and directly with IGFBP-1 (r=0.52, P <0.05), whereas no correlation between cortisol and IGF system-related variables was observed in IUGR. Finally, in IUGR children an inverse correlation was found between length gain in the first trimester of life and cortisol concentrations at birth (r=-0.54, P < 0.005). CONCLUSIONS: Cortisol might be a physiological regulator of fetal growth, at least in the last part of pregnancy, by modulating IGF-I and IGFBP-1 release under conditions of fetal stress. In IUGR children, a rearrangement of this growth control mechanism seems to occur. The close inverse relationship of cortisol with linear growth, if confirmed by large-scale studies, suggests cord blood cortisol to be potentially predictive of early postnatal catch-up growth in IUGR infants.
Calcitonin levels are similar in goitrous euthyroid patients with or without thyroid antibodies, as well as in hypothyroid patients
Authors: Pantazi H , Papapetrou PD
Published: January 2005

OBJECTIVE: Some authors, after studying retrospectively immunostained sections of thyroid specimens, found C-cell hyperplasia (CCH) unrelated to medullary thyroid carcinoma to be frequent in thyroid glands affected by chronic lymphocytic thyroiditis (CLT); others failed to observe this association. The purpose of the present study was to further investigate prospectively the existence of the proposed relationship between CLT and CCH by measuring circulating calcitonin (CT) levels. DESIGN: Basal serum CT was measured in 174 euthyroid goitrous women with negative thyroid autoantibodies (TA-Neg) and 124 age-matched goitrous euthyroid women with positive antibodies (TA-Pos). A calcium-infusion test was performed in 27 TA-Neg and 31 TA-Pos age-matched euthyroid goitrous women. Basal CT was also determined in 51 hypothyroid women and 40 control normal healthy women. METHODS: Serum CT was measured using a specific and sensitive two-site immunoassay which detects mainly the CT-32 monomer. Thyroid autoantibodies (anti-thyroid peroxidase and anti-thyroglobulin) were measured in serum by quantitative RIAs. RESULTS: Basal serum CT was found to be similar in TA-Neg and TA-Pos euthyroid as well as hypothyroid and normal control groups. A test of independence performed on the frequency distribution of the patients among sequential classes of serum CT showed that basal CT levels are independent of the presence of thyroid autoantibodies or hypothyroidism. Calcium-stimulated CT as well as the increase in CT were similar in TA-Neg and TA-Pos euthyroid goitrous women. There was no correlation between thyrotropin and CT in the hypothyroid group. CONCLUSION: Positive thyroid antibodies in goitrous patients do not predispose to hypercalcitoninemia. Elevated CT found in a patient with goitre and positive thyroid antibodies should not be ascribed to the underlying thyroiditis; this patient should be investigated for some other cause of the high CT.
Thyroid size and thyroid function during pregnancy: an analysis
Authors: Berghout A , Wiersinga W
Published: January 2005

An analysis of all available studies of thyroid size and function in pregnancy reveals that thyroid size, estimated by inspection and palpation or measured more accurately by ultrasonography, increases in pregnancy in areas of iodine deficiency but not in those with sufficient iodine. The increase in average thyroid size is within the normal range, and can partly be prevented by treatment with extra iodine or thyroxine. There is a slight transient increase in free thyroxine in the first trimester, probably as a result of physiological stimulation of thyroid function by human choriogonadotrophin. These levels then decrease by about 30% to low normal values in the second and third trimesters of pregnancy in both iodine-depleted and -replete areas. These changes resemble those of non-thyroidal illness and may well play a role in reducing energy expenditure during pregnancy. The increase in thyroid size in iodine-deficient areas is probably due to autoregulatory mechanisms of iodine on thyroid growth. The hypothesis is supported by the fact that, during pregnancy, thyroid volume and thyroid function adapt in a physiological way to meet the increased demands for iodine and energy.