bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of pegylated human recombinant leptin (PEG-OB) on neuroendocrine adaptations to semi-starvation in overweight men
Authors: Hukshorn CJ , Menheere PP , Westerterp-Plantenga MS , Saris WH
Published: January 2005

OBJECTIVE: Starvation induces a complex neuroendocrine response in humans thought to have evolved to defend against reduced energy intake. The drop in leptin levels observed during fasting has been implicated as a factor that triggers this adaptive response. To explore this hypothesis, we executed a randomized, double-blind, placebo-controlled study to investigate whether elevated leptin levels using long-acting pegylated human recombinant leptin (PEG-OB) influenced the neuroendocrine responses to semi-starvation in human subjects. DESIGN: Twenty-four overweight male subjects (mean+/-s.e.m.; 34.8+/-1.3 yrs; 28.8+/-0.5 kg/m(2)) were prescribed a very low energy diet (2.1 MJ/day) to induce a state of semi-starvation for the next 46 days. In addition, all subjects received a weekly treatment of 80 mg PEG-OB or matching placebo. Hormone measurements were performed throughout the study period and included 5-h frequent hormone samplings and 24-h urine collections. RESULTS: Weekly subcutaneous administration of PEG-OB led to significant additional weight loss (2.8 kg) but it did not reverse the fasting-induced changes in the thyroid, corticotropic, somatotropic axes and sympathetic nervous system activity. However, after adjustment for weight loss, the drop in mean luteinizing hormone levels was attenuated in the PEG-OB group compared with the placebo group. CONCLUSIONS: These results suggest that a reduced level of leptin accompanying food restriction might be a component of the fasting-induced neuroendocrine inhibition of the human reproductive axis.
Decreased plasma adiponectin concentrations in women with low-grade C-reactive protein elevation
Authors: Matsubara M , Namioka K , Katayose S
Published: January 2005

OBJECTIVE: Inflammation has been suggested as a risk factor for the development of atherosclerosis, while some components of metabolic syndrome X have been related to inflammatory markers. We hypothesized that adipocyte secreting protein, adiponectin and leptin, for which have been demonstrated an association with metabolic syndrome X and coronary artery disease, may be associated with inflammatory markers in nondiabetic humans. DESIGN AND METHODS: We measured high-sensitivity C-reactive protein (hs-CRP), as an inflammatory marker, and adiponectin and leptin concentrations in 384 nondiabetic Japanese women (mean+/-s.e.m. age 53.6+/-0.8 Years, body mass index (BMI) 23.0+/-0.2 kg/m(2)) undergoing measurement of markers of metabolic syndrome X. RESULTS: The women who had a low-grade hs-CRP elevation (>2.0 mg/l) were significantly older and had higher BMI, body fat mass (BFM), total cholesterol (TC), triglyceride (TG), atherogenic index (AI=(TC-HDLC)/HDLC), where HDLC is high-density lipoproten-cholesterol), fasting blood glucose and leptin concentrations before and after adjustment for BMI or BFM, while lower HDLC and adiponectin concentrations before and after adjustment compared with women with normal CRP levels (<0.5 mg/l). BMI, BFM, TG, AI and leptin before and after adjustment were found to be correlated with hs-CRP levels, while HDLC and adiponectin before and after adjustment were inversely correlated (all P<0.0001). hs-CRP was independently associated with white blood cell count, blood urea nitrogen and AI and inversely with adiponectin/BFM in the stepwise regression analysis model. CONCLUSIONS: These data demonstrate a significant decrease in plasma adiponectin in low-grade chronic inflammation, and suggest that there is an important linkage between inflammation/adipose tIssue/atherosclerosis.
Intralipid/heparin infusion suppresses serum leptin in humans
Authors: Garcia-Lorda P , Nash W , Roche A , Pi-Sunyer FX , Laferrere B
Published: January 2005

BACKGROUND/AIM: Our previous studies showed that administration of dexamethasone plus food increased serum leptin levels 100% more than dexamethasone alone. We hypothesized that this increase in leptin from the meal could result directly from the provision of fuel metabolites rather than from the meal-induced rise in insulin. In the current study, we tested the effect of an i.v. lipid fuel source (Intralipid 20%/heparin) that would incur only a modest increase in insulin. This study was undertaken because the role of lipid in the regulation of human leptin levels has been controversial, with differing effects reported: stimulatory, inhibitory, or no effect at all. METHODS: In order to evaluate how lipids affect serum leptin in humans, we administered the following to seven lean, healthy, fasting subjects: (i) Intralipid 20% at 0.83 ml/kg.h plus heparin (800 IE/h) infused i.v. for 7 h (LIPID), (ii) LIPID with one initial pulse of insulin (0.09 U/kg) given s.c. (LIPID+INS), (iii) LIPID with dexamethasone (2 mg i.v. push) given at the start of the infusion (LIPID+DEX), and (iv) LIPID with insulin plus dexamethasone (LIPID+INS+DEX). Control trials in another 14 subjects matched hormonal conditions but lacked the LIPID infusion. Blood levels were collected over 8 h for determination of free fatty acids (FFA), glucose, insulin, and leptin under each experimental condition. RESULTS: Over the 420 min of LIPID infusion, FFA levels rose four-fold from 0.28+/-0.05 mmol/l to 0.99+/-0.05 mmol/l. Serum leptin levels were suppressed by 10-20% in the LIPID condition as compared with control (no LIPID) between 90 min (P=0.008) and 360 min (P=0.045). LIPID+DEX did not increase leptin. A pulse of insulin (INS) increased serum insulin levels to 49.9+/-6.1 U/ml at 90 min and increased serum leptin by 21.3+/-6.6% at 480 min (P=0.054). LIPID decreased leptin in the face of this insulin-induced increase (LIPID+INS), between 360 min (P=0.017) and 420 min (P=0.003), with a 23% suppressive effect at 420 min. LIPID+DEX elevated leptin levels by 112.5+/-35.8% at 480 min (P=0.037), however, the Intralipid/heparin infusion did not blunt the rise of leptin under these conditions. CONCLUSIONS: These data showed that Intralipid/heparin: (i) are not sufficient to trigger the effect of dexamethasone on leptin, (ii) have an acute inhibitory effect on both fasting and insulin-stimulated leptin levels, and (iii) that this inhibitory effect cannot reverse the strong stimulatory effect of dexamethasone and insulin on serum leptin.
Update on the diagnosis of GH deficiency in adults
Authors: Abs R
Published: January 2005

GH deficiency (GHD) in adults is associated with considerable morbidity and mortality. The diagnosis of GHD is generally straightforward in children as growth retardation is present; however, in adults, diagnosis of GHD is often challenging. Other markers are therefore needed to identify adults who have GHD and could potentially benefit from GH replacement therapy. Consensus guidelines for the diagnosis and treatment of adult GHD recommend provocative testing of GH secretion for patients who have evidence of hypothalamic-pituitary disease, patients with childhood-onset GHD, and patients who have undergone cranial irradiation or have a history of head trauma. Suspicion of GHD is also heightened in the presence of other pituitary hormone deficits. Tests for GHD include measurement of the hormone in urine or serum or measurement of stimulated GH levels after administration of various provocative agents. The results of several studies indicate that non-stimulated serum or urine measurements of GH levels cannot reliably predict deficiency in adults. Although glucagon and arginine tests produce a pronounced GH response with few false positives, the insulin tolerance test (ITT) is currently considered to be the gold standard of the GH stimulation tests available. Unfortunately, the ITT has some disadvantages and questionable reproducibility, which have prompted the development of several new tests for GHD that are based on pharmacological stimuli. Of these, GH-releasing hormone (GHRH) plus arginine and GHRH plus GH-releasing peptide (GHRP) appear to be reliable and practical. Thus, in cases where ITT is contraindicated or inconclusive, the combination of arginine and GHRH is an effective alternative. As experience with this test as well as with GHRH/GHRP-6 accumulates, they may supplant ITT as the diagnostic test of choice.
Long-term experience with GH replacement therapy: efficacy and safety
Authors: Monson JP
Published: January 2005

Demonstration of the long-term efficacy of GH replacement in GH-deficient adults has depended on a combination of single-centre studies and data from large multinational databases, which, by virtue of their size, are likely to detect rare adverse events and also permit analysis of mortality rates. The Pharmacia International Metabolic Surveillance (KIMS) study (a pharmacoepidemiological survey of the safety and efficacy of GH replacement in adults, sponsored by Pharmacia) is currently the largest database, with information on over 8000 patients from a total of 27 countries. Abundant epidemiological evidence confirms that hypopituitarism is associated with premature mortality, with an increase in cardiovascular and cerebrovascular disease as a primary underlying cause. Central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus are common in adults with hypopituitarism. GH replacement is associated with improvements in central fat mass and mean reductions in serum total and low-density lipoprotein cholesterol which may be additive to those achieved with hydroxymethylglutaryl-coenzyme A reductase inhibitors. These beneficial effects are maintained for at least 2 Years after initiation of therapy, as are reductions in central adiposity, with similar benefits seen in men and women when the GH dose is titrated to achieve a serum IGF-I between the median and the upper end of the age-related reference range. Fasting plasma glucose and glycated haemoglobin increase, usually within the reference range, during prolonged GH replacement, but do not tend to rise further above baseline in subjects with pre-existing impaired glucose tolerance. Bone remodelling increases during GH replacement therapy, but indices tend to return to baseline within 5 Years of commencing treatment. Bone mineral density increases in men whereas, in women, improvement is limited to stabilisation of bone density. Data from the KIMS study demonstrate that prolonged GH replacement is associated with a reduction in the number of patients requiring assistance with daily living and a significant reduction in sick leave and hospital admissions. GH replacement therapy improves psychological well-being, particularly in those patients with the greatest deficit prior to treatment, with improvement maintained beyond 6 Months of therapy and sustained during long-term follow-up. Data from the KIMS population show that there is no increase in the overall occurrence of de novo neoplasia or the rate of regrowth of primary pituitary tumours. There is an apparent increase in intracranial neoplasia, which may be an artefact of comparing a surveillance population with general population data. Unlike mortality in untreated hypopituitary GH-deficient patients, mortality in the KIMS study is currently similar to that predicted for the normal population.
Insulin-like growth factor-I: marker for diagnosis of acromegaly and monitoring the efficacy of treatment
Authors: Brabant G
Published: January 2005

Acromegaly is caused by chronic excess secretion of growth hormone (GH) and resultant persistent elevation in concentrations of insulin-like growth factor-I (IGF-I), also called somatomedin-C. A number of diagnostic tests are available to support the diagnosis of acromegaly, but those that rely on measurement of serum GH concentrations have important limitations. Concentrations of serum IGF-I, which is produced principally in the liver and mediates the actions of GH, have been shown to correlate with clinical and metabolic markers of disease activity. Additionally, normalisation of IGF-I levels in acromegaly is associated with the resolution of symptoms and normal life expectancy. Thus, serum IGF-I is an important marker of disease activity and a sensitive, practical, and reliable measure of integrated GH concentrations in patients with acromegaly.
In congenital hypothyroidism bone maturation at birth may be a predictive factor of psychomotor development during the first Year of life irrespective of other variables related to treatment
Authors: Wasniewska M , De Luca F , Cassio A , Oggiaro N , Gianino P , Delvecchio M , Aiazzi R , Stoppioni V , Lombardo F , Messina MF , Valenzise M , Arrigo T
Published: January 2005

OBJECTIVE: To evaluate in a cohort of infants with congenital hypothyroidism (CH): (a) the frequency of bone maturation (BM) retardation at birth and (b) whether BM delay at birth may be considered as a tool to make a prognosis of psychomotor status at the age of 1 Year, irrespective of other variables related to treatment. DESIGN: BM at birth, CH severity and developmental quotient (DQ) at the age of 1 Year were retrospectively evaluated in 192 CH infants selected by the following inclusion criteria: (a) gestation age ranging between 38 and 42 weeks; (b) onset of therapy within the first Month of life; (c) initial thyroxine (l-T(4)) dosage ranging from 10 to 12 microg/kg/day; (d) normalization of serum thyrotropin (TSH) levels before the age of 3 Months; (e) Monthly adjustments of l-T(4) dose during the first Year of life with serum TSH levels ranging from 0.5 to 4 mIU/l; (f) no major diseases and/or physical handicaps associated with CH; (g) availability of both thyroid scanning and knee X-rays at the time of treatment initiation; (h) availability of DQ assessment at an average age of 12 Months. METHODS: BM was considered normal if the distal femur bony nucleus diameter exceeded 3 mm (group A) or retarded if either this nucleus was absent (subgroup B1) or its diameter was <3 mm (subgroup B2). DQ was evaluated with the Brunet-Lezine test. RESULTS: In 44.3% of cases BM was either delayed (23.5%) or severely delayed (20.8%). The risk of BM retardation was higher in the patients with athyreosis than in the remaining patients (41/57 vs 44/135, chi(2)=25.13, P<0.005). BM-retarded infants showed a more severe biochemical picture of CH at birth and a lower DQ at the age of one Year compared with the group A patients. If compared with infants of subgroup B2 those of subgroup B1 exhibited significantly lower T(4) levels at birth and a more frequent association with athyreosis (70.0 vs 30.0%; chi(2)=7.49, P<0.01), whereas DQ was superimposable in both subgroups. CONCLUSIONS: (a) BM at birth is delayed in almost half of CH patients and (b) CH severity per se can affect DQ at the age of 1 Year irrespective of other variables related to therapy.
Role of gamma probes in performing minimally invasive parathyroidectomy in patients with primary hyperparathyroidism: optimization of preoperative and intraoperative procedures
Authors: Rubello D , Piotto A , Casara D , Muzzio PC , Shapiro B , Pelizzo MR
Published: January 2005

OBJECTIVE: In the last decade, surgery of primary hyperparathyroidism (HPT) due to a solitary adenoma has moved on from the traditional wide bilateral neck exploration (BNE) to more limited approaches such as unilateral neck exploration and minimally invasive parathyroidectomy. DESIGN: To define the role of intraoperative gamma probe and injection of a low (99m)Tc-MIBI dose in performing minimally invasive radio-guided surgery (MIRS) in HPT patients with a solitary parathyroid adenoma. METHODS: From September 1999 to July 2002, 214 patients with primary HPT entered the study. All patients were preoperatively investigated by a (99m)Tc-pertechnetate/MIBI subtraction scan and high-resolution neck ultrasound. The intraoperative technique we developed differs from other previously described techniques being based on the injection of a low (37 MBq) MIBI dose in the operating theatre a few minutes before the beginning of intervention. RESULTS: On the basis of scan/ultrasound findings 147 patients were selected for a MIRS and 144 of them (98%) were successfully treated by this approach: a solitary parathyroid adenoma was removed through a small 2-2.5 cm skin incision with a mean operative time of 35 min, and a mean hospital stay of 1.2 days. In the other 67 patients with scan/ultrasound evidence of concomitant nodular goiter (n=45) or multi-gland disease (n=13) or with a negative scan (n=9), the gamma probe was utilized during a traditional BNE. A low 37 MBq MIBI dose proved to be sufficient to perform a MIRS; moreover it delivered to the patient and surgeon a low, negligible, radiation exposure dose. CONCLUSIONS: The combination of a (99m)Tc-pertechnetate/MIBI subtraction scan and neck ultrasound appears to be an accurate imaging protocol in selecting primary HPT patients as candidates for a MIRS. A MIBI dose as low as 37 MBq injected in the operating theatre just before the start of surgery appears to be adequate to perform radio-guided surgery.
Development of acromegaly in patients with prolactinomas
Authors: Andersen M , Hagen C , Frystyk J , Schroeder HD , Hagen C
Published: January 2005

OBJECTIVES: Patients with prolactinomas and patients with acromegaly often have heterogenous adenomas. In this study we have focused on patients with prolactinomas who developed acromegaly and acromegalic patients with hyperprolactinaemia. Our hypothesis is that some patients with hyperprolactinaemia may develop clinical acromegaly. METHODS: We have included patients examined at department M, Odense University Hospital between 1996 and 2001. Seventy-eight patients with prolactinomas, 65 females and 13 males, with a median age (range) of 30 Years (14-74) and 47 Years (20-66), respectively, were included in the study. RESULTS: In females and males the median prolactin (PRL) levels were 90 microg/l (27-4700; normal values (NV) <or=23) and 1075 microg/l (24-6500; NV <or=14), respectively. The PRL levels were significantly higher in males compared with females (P<0.002). Fifty-nine patients with acromegaly, 24 females and 35 males, with a median age (range) of 45 Years (24-70) and 53 Years (19-70), respectively, were included. Seven of the 24 females had hyperprolactinaemia, with PRL levels of 90 microg/l (27-494). Thirteen of the 35 males had hyperprolactinaemia with PRL levels of 47 microg/l (17-251). Three females with prolactinomas developed acromegaly clinically and biochemically. These patients had a normal low GH level and/or a normal IGF-I level at first diagnosis. CONCLUSIONS: Our findings suggest that there is a common group of patients with a pituitary adenoma who secrete PRL and GH unsynchronously. Some of these patients have clinical acromegaly at diagnosis and some patients diagnosed as prolactinomas will develop acromegaly. We suggest an annual IGF-I measurement as a screening test.
The human chorionic gonadotropin test is more powerful than the gonadotropin-releasing hormone agonist test to discriminate male isolated hypogonadotropic hypogonadism from constitutional delayed puberty
Authors: Degros V , Cortet-Rudelli C , Soudan B , Dewailly D
Published: January 2005

OBJECTIVE: The effectiveness of biological investigations aiming at discriminating isolated hypogonadotropic hypogonadism (IHH) from constitutional delayed puberty (CDP) in male patients is still controversial. We revisited the diagnostic power of the basal serum testosterone level, the Triptorelin test and the human chorionic gonadotropin (hCG) test in a cohort of 33 boys with delayed puberty. DESIGN: Boys were aged 14.2 to 26.2 Years at referral. A 5-Year-long clinical follow-up after the initial study allowed confirmation of the diagnosis. At the end of the follow-up period, IHH was found in 13 patients while the other 20 had normal spontaneous pubertal development (CDP). RESULTS: At referral, a basal morning testosterone level >1.7 nmol/l was observed in 55% of patients with CDP exclusively (predictive positive value (PPV)=100%; predictive negative value (PNV)=59%). For CDP, the PPV of the LH peak 3 h after Triptorelin was 100% by setting the upper threshold at 14 IU/l and the PNV was 72%. However, no lower threshold could discriminate IHH from CDP in the remaining patients with an LH peak 3 h after Triptorelin <14 IU/l. In CDP patients, the PPV of the serum testosterone increment after hCG stimulation (deltaT/hCG) was 100% for values >9 nmol/l (PNV=72%). In IHH patients, the PPV of deltaT/hCG was 100% for values <3 nmol/l (PNV=82%). Only 29% of the studied population had a deltaT/hCG between these lower and upper thresholds and therefore could not have been classified initially. CONCLUSIONS: (i) Dynamic testing for the diagnosis of delayed puberty is useful only when the basal testosterone level is lower than 1.7 nmol/l; (ii) in that case, the hCG test has better discriminating power than the Triptorelin test and appears as the best cost-effective investigation. It prevents useless and expensive investigations in about one-half of CDP patients with a basal morning testosterone level lower than 1.7 nmol/l.
Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications
Authors: Knudsen ST , Foss CH , Poulsen PL , Andersen NH , Mogensen CE , Rasmussen LM
Published: January 2005

OBJECTIVE: Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Plasma levels of OPG seem to be elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. The aim of the present study was to examine the association between plasma OPG levels and microvascular complications and glycemic control in patients with type 2 diabetes. DESIGN AND METHODS: Four groups of 20 subjects in each, individually matched for age and gender, were included in the study: (i) subjects with normal glucose tolerance (NGT); (ii) subjects with impaired glucose tolerance (IGT); (iii) type 2 diabetic patients without retinopathy; and (iv) type 2 diabetic patients with diabetic maculopathy (DMa). Plasma concentration of OPG was measured in duplicate by a sandwich ELISA method. Furthermore, fundus photography, flourescein angiography, and measurements of urinary albumin excretion rate (RIA) were performed. RESULTS: Plasma OPG was significantly higher in diabetic (iii+iv) than in NGT (i) subjects (3.04+/-0.15 vs 2.54+/-0.16 ng/ml, P<0.05). Plasma OPG was significantly higher in the DMa (iv) group than in the NGT (i) group (3.25+/-0.23 vs 2.54+/-0.16 ng/ml, P=0.01). Moreover, plasma OPG was significantly higher (3.61+/-0.36 ng/ml) in the group of diabetic subjects with both microalbuminuria and DMa (n=7) than in the NGT (i) (2.54+/-0.16 ng/ml, P<0.01), IGT (ii) (2.82+/-0.21 ng/ml, P<0.05), and no retinopathy (iii) groups (2.83+/-0.20 ng/ml, P<0.05). CONCLUSIONS: We found increased levels of OPG in plasma from diabetic patients with microvascular complications. This finding indicates that OPG may be involved in the development of vascular dysfunction in diabetes [corrected].
Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia
Authors: Lombardo F , De Luca F , Rosano M , Sferlazzas C , Lucanto C , Arrigo T , Messina MF , Crisafulli G , Wasniewska M , Valenzise M , Cucinotta D
Published: January 2005

OBJECTIVE: The loss of pancreatic beta-cells is thought to be one of the principal causes of diabetes mellitus (DM) in cystic fibrosis (CF), but the role of peripheral insulin resistance (IR) in the pathogenesis of DM in CF remains unclear. The aim of this study was to evaluate whether eventual changes of glucose tolerance (GT) over time were associated with modifications of insulin secretion or sensitivity. METHODS: Plasma glucose and insulin responses to an oral GT test (OGTT) were investigated and reinvestigated 13 Years later in 14 CF patients with initial and persistent fasting euglycemia and no history of insulin treatment. Insulin sensitivity (IS) at both tests was assessed on the basis of insulin and glucose levels both in the fasting state and during OGTTs. RESULTS: From the 1st to the 2nd OGTT: (a) the prevalence of DM responses significantly increased; (b) the areas beneath the respective glucose and insulin curves significantly increased and decreased respectively; (c) IR and IS indices decreased and increased respectively, even in the patients who developed DM; (d) pulmonary function significantly worsened in the entire series, especially in the patients who developed DM. CONCLUSIONS: (i) the natural history of glyco-metabolic status in CF is characterized by deteriorating GT over time; (ii) insulinopenia plays a prominent role in the pathogenesis of GT worsening; (iii) IR does not play any significant part in the pathogenesis of DM development; (iv) deterioration of lung function tests is more severe in the subjects who develop DM over time.
Nitric oxide stimulates glucose transport through insulin-independent GLUT4 translocation in 3T3-L1 adipocytes
Authors: Tanaka T , Nakatani K , Morioka K , Urakawa H , Maruyama N , Kitagawa N , Katsuki A , Araki-Sasaki R , Hori Y , Gabazza EC , Yano Y , Wada H , Nobori T , Sumida Y , Adachi Y
Published: January 2005

OBJECTIVE: It is well known that nitric oxide synthase (NOS) is expressed and that it modulates glucose transport in skeletal muscles. Recent studies have shown that adipose tIssues also express inducible and endothelial nitric oxide synthase (eNOS). In the present study, we investigated whether nitric oxide (NO) induces glucose uptake in adipocytes, and the signaling pathway involved in the NO-stimulated glucose uptake in 3T3-L1 adipocytes. METHODS: First, we determined the expression of eNOS in 3T3-L1 adipocytes, and then these cells were treated with the NO donor sodium nitroprusside (SNP) and/or insulin, and glucose uptake and phosphorylation of insulin receptor substrate (IRS)-1 and Akt were evaluated. Moreover, we examined the effects of a NO scavenger, a guanylate cyclase inhibitor or dexamethasone on SNP-stimulated glucose uptake and GLUT4 translocation. RESULTS: SNP at a concentration of 50 mmol/l increased 2-deoxyglucose uptake (1.8-fold) without phosphorylation of IRS-1 and Akt. Treatment with the NO scavenger or guanylate cyclase inhibitor decreased SNP-stimulated glucose uptake to the basal level. Dexamethasone reduced both insulin- and SNP-stimulated glucose uptake with impairment of GLUT4 translocation. CONCLUSION: NO is capable of stimulating glucose transport through GLUT4 translocation in 3T3-L1 adipocytes, via a mechanism different from the insulin signaling pathway.
The involvement of apoptotic regulators during in vitro decidualization
Authors: Akcali KC , Gibori G , Khan SA
Published: January 2005

OBJECTIVES: The uterus responds to an implanting blastocyst by undergoing extensive tIssue modification leading to decidualization. This modification includes differentiation and apoptosis of epithelial as well as stromal cell compartments. It is generally accepted that the decidual cell regression pattern is similar to the pattern of initial differentiation, suggesting that decidual cell death is the end point of timed differentiation. However, the molecular mechanisms controlling these events are not understood clearly. Therefore, we aimed to investigate the involvement of apoptotic factors using an in vitro cell culture system. DESIGN: In order to assess the role of apoptotic factors during decidualization, we used a decidual cell line (GG-AD) that had been transformed with a temperature-sensitive SV-40 mutant. At the non-permissive temperature (39 degrees C), these cells showed the characteristics of differentiated decidual cells. They dedifferentiated into stromal cells when the temperature was shifted back to 33 degrees C. METHODS: We performed Northern blot analysis for bax, bcl-x(L) and bcl-2 at both temperatures. The onset of apoptosis was examined by Annexin V staining. The expression of p53 protein was also determined by Western blot. RESULTS: We found an increase in the expression of bax when GG-AD cells were grown at 39 degrees C. We also showed apoptosis with Annexin V staining at 39 degrees C. The p53 protein expression was also similar to that of the animal models, suggesting that the programmed cell death of the decidual cells occurred in a p53-independent manner. CONCLUSIONS: These data indicate that a parallelism exists between the increased expression of pro-apoptotic genes and decidual cell death, similar to animal models. Therefore, an in vitro model of GG-AD cells can be used to assess directly the relationship between apoptotic regulators and decidualization and could be used to study the mechanism of decidual cell regression.
Intrinsic imperfections of endocrine replacement therapy
Authors: Romijn JA , Smit JW , Lamberts SW
Published: January 2005

Hormonal substitution therapy has been extremely successful, with respect to morbidity and mortality, in the treatment of the major syndromes of endocrine insufficiency. However, many patients treated for endocrine insufficiencies still suffer from more or less vague complaints and a decreased quality of life. It is likely that these complaints are, at least in part, caused by intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. Unfortunately, these complaints are often difficult to assess by clinicometric or biochemical tests, because the effects of hormones in general, and thus of hormone replacement strategies in particular, are difficult to quantify at the tIssue level. Therefore, in clinical practice we rely mostly on plasma variables - 'plasma endocrinology' - which are a poor reflection of hormone action at the tIssue level. Appreciation of these intrinsic shortcomings of endocrine therapy is of utmost importance to prevent incorrect labelling of the complaints of many endocrine patients and to achieve further improvement in endocrine replacement strategies.
Evolution of thyroid autoimmunity during iodine prophylaxis--the Sri Lankan experience
Authors: Mazziotti G , Premawardhana LD , Parkes AB , Adams H , Smyth PP , Smith DF , Kaluarachi WN , Wijeyaratne CN , Jayasinghe A , de Silva DG , Lazarus JH
Published: January 2005

OBJECTIVE: To study the evolution of thyroid autoimmunity, in relation to the change in goitre prevalence, during 3 Years of iodine prophylaxis in Sri Lanka. METHODS: Two groups of Sri Lankan schoolgirls between the ages of 10.8 and 17.5 Years were studied in 1998 (401 girls) and 2001 (282 girls). A prospective study was performed in 42 schoolgirls who were thyroid autoantibody (Ab)-positive (+ve) in 1998. Anthropometric measures, urinary iodine excretion (UIE), thyroid Volume, free thyroxine, free tri-iodothyronine, TSH, and thyroglobulin (Tg) and thyroid peroxidase (TPO) Ab were evaluated in all 683 girls. RESULTS: Goitre prevalence was significantly lower in 2001 compared with 1998 related to age (2.9% compared with 20.2%) and body surface area (11.6% compared with 40.8%), although UIE was unchanged. Prevalence of thyroid Ab in 2001 was also lower (23.4% compared with 49.9%); among those with the Ab, 34.8% had TgAb alone and 46.9% had a combination of TgAb+TPOAb, compared with 82.0% TgAb alone in 1998. In 2001, subclinical hypothyroidism was more frequent in Ab+ve (6.3%) than Ab-negative girls (1.0%). A cohort of 42 Ab+ve schoolgirls in 1998 (34 with TgAb alone, eight with TgAb+TPOAb) were evaluated again in 2001. Only 10 of them (23.8%) remained Ab+ve (mostly TPOAb+/-TgAb) in 2001. CONCLUSIONS: This study demonstrates that: (1) in 2001, goitre prevalence and thyroid autoimmunity rates were significantly lower than in 1998; (2) the pattern of thyroid Ab was different in the two surveys; (3) in 2001 alone, the occurrence of hypothyroidism was correlated with the presence of thyroid autoimmunity. These results indicate an evolution of thyroid autoimmune markers during the course of iodine prophylaxis, which has not been described before.
Circulating levels of ghrelin in human fetuses
Authors: Cortelazzi D , Cappiello V , Morpurgo PS , Ronzoni S , Nobile De Santis MS , Cetin I , Beck-Peccoz P , Spada A
Published: January 2005

OBJECTIVE: Ghrelin is a GH secretagog isolated recently from rat stomach and involved in the stimulation of food intake and adiposity in rodents and humans. Moreover, subsequent studies showed that ghrelin is expressed in rat and human placenta, suggesting a possible influence of the peptide on fetal growth. The aim of this study was to evaluate circulating levels of ghrelin in appropriate for gestational age (AGA) or intrauterine growth-restricted (IUGR) fetuses. SUBJECTS AND METHODS: Ghrelin levels between 20 and 39 weeks of gestation were measured in 16 AGA and nine IUGR fetuses in whom blood was collected by cordocentesis performed for prenatal diagnosis of different diseases or during elective cesarean section. In most samples, GH, cortisol and leptin levels were also evaluated. Results are expressed as means+/-S.D. Differences were tested using the Student's t-test with Welch correction. P<0.05 was considered significant. RESULTS: All fetuses showed levels of ghrelin in the umbilical venous blood (100+/-99 pmol/l) that did not correlate with the gestational age or the maternal ghrelin levels. No difference was found between umbilical venous and arterial concentrations, suggesting that fetal tIssues are a source of ghrelin. Ghrelin levels in IUGR fetuses were significantly higher than those found in AGA fetuses (176+/-125 vs 58+/-44 pmol/l; P<0.005). Moreover, in samples obtained at birth, ghrelin concentrations correlated negatively with birth weight (P<0.05). In IUGR fetuses, GH and cortisol concentrations were higher and leptin levels lower than in AGA fetuses, although no significant correlation between these parameters and ghrelin levels was found. CONCLUSION: The presence of ghrelin in the fetal circulation as well as its increase in IUGR fetuses suggest a role of this peptide during intrauterine development.
A survey of pituitary incidentaloma in Japan
Authors: Sanno N , Oyama K , Tahara S , Teramoto A , Kato Y
Published: January 2005

OBJECTIVE: The development of computed tomography (CT) and magnetic resonance imaging (MRI) has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (pituitary incidentalomas). The aim of this study was to perform a national survey on pituitary incidentalomas in order to establish an appropriate approach to them. DESIGN AND METHODS: Five hundred and six patients with pituitary incidentalomas were obtained by questionnaire from March 1999 to May 2000 under the auspices of the Ministry of Health, Labor and Welfare in Japan. Two hundred and fifty-eight patients underwent surgery (surgical group), while 248 patients were followed up conservatively for a mean period of 26.9 Months (range 6-173 Months) (non-surgical group). Clinical and biochemical assessment, CT or MRI of the pituitary, and visual field testing by Goldman perimetry were assessed at baseline and 6 Months and Yearly thereafter. RESULTS: Thirty-three patients with pituitary incidentalomas (13.3%) developed tumor enlargement during the mean follow-up period of 45.5 Months. Of 115 estimated non-functioning adenomas, 23 tumors (20.0%) increased during a mean follow-up period of 50.7 Months (range 10-173 Months), while 5 of 94 (5.3%) estimated Rathke's cysts increased in size during follow-up. Pituitary apoplexy occurred in one of 248 patients (0.4%). CONCLUSIONS: Pituitary incidentalomas usually follow a benign course. We recommend transsphenoidal adenectomy for a solid mass attached to the optic chiasma estimated to be a pituitary adenoma by MRI. Other patients should be followed up by MRI every 6 Months for the first 2 Years, and then Yearly.
Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease
Authors: Dolzan V , Stopar-Obreza M , Zerjav-Tansek M , Breskvar K , Krzisnik C , Battelino T
Published: January 2005

OBJECTIVE: To analyse the mutational spectrum, the associated haplotypes and the genotype-phenotype correlation, and to design a reliable and rational approach for CYP21 mutation detection in Slovenian congenital adrenal hyperplasia (CAH) patients. DESIGN: Molecular analysis of the CYP21 gene was performed in 36 CAH patients and 79 family members. METHODS: Southern blotting, sequence-specific PCR amplification (PCR-SSP), sequence-specific oligonucleotide hybridisation (PCR-SSO) and sequencing were used to detect CYP21 gene deletions, conversions and point mutations. RESULTS: CYP21 gene deletion was the most frequent mutation (36.4%). Large gene conversions detectable only by Southern blotting represented 12.1%, and gene conversions involving the promoter region represented 7.6% of the mutated alleles. The most frequent point mutations were: intron 2 splice mutation 16.7%, Ile172Asn mutation 7.6%, Gln318Stop 7.5% and Pro30Leu 12.2% of alleles. A correlation between the genotype and the clinical phenotype similar to those described for large populations was observed. The finding of Pro30Leu mutation linked to a gene conversion could explain the simple virilising (SV) phenotype in compound heterozygotes for the Pro30Leu and a severe mutation. In two siblings with a salt wasting form of CAH (SW-CAH), a novel mutation Ala15Thr was found on the allele characterised by Pro30Leu mutation and gene conversion involving the promoter region. CONCLUSIONS: Our genotyping approach allowed reliable diagnosis of CAH in the Slovenian population. The high frequency of CYP21 gene aberrations on Pro30Leu positive alleles justified systematic searching for a gene conversion in the promoter region using the PCR-SSP reaction.
The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromso Study
Authors: Svartberg J , Midtby M , Bonaa KH , Sundsfjord J , Joakimsen RM , Jorde R
Published: January 2005

OBJECTIVE: To study whether lifestyle factors and/or chronic disease are associated with the age-related decline of total and free testosterone in men, or if these factors might be associated with the variation of total and free testosterone but not with their age-related decline. DESIGN: A population-based, cross-sectional study was used. METHODS: Total testosterone and sex hormone binding globulin (SHBG) levels were analyzed and free testosterone levels were calculated in 1563 men participating in the Tromso study in 1994/1995. Anthropometric characteristics were also measured and two standardized questionnaires completed, including lifestyle factors and medical history. The data were analyzed with multiple linear regression analysis of covariance, and logistic regression. RESULTS: Total and free testosterone were inversely associated (P=0.001 and P<0.001), while SHBG was positively associated (P<0.001) with age. Body mass index (BMI) was inversely associated with total (P<0.001) and free (P=0.016) testosterone and SHBG (P<0.001). Both total and free testosterone were positively associated with tobacco consumption (P<0.001 and P=0.004) and total testosterone was positively associated with coffee consumption (P<0.001). SHBG was positively associated with smoking (P=0.004) and coffee consumption (P<0.001). Men who reported having had a stroke or having a cancer diagnosis had lower levels of total testosterone (P<0.001 and P<0.01) and free testosterone (P<0.01). CONCLUSIONS: BMI and smoking are independent contributors to the variation of total and free testosterone and SHBG levels, and coffee consumption to the variation of total testosterone and SHBG. Thus, lifestyle factors can have a direct effect on circulating levels of free endogenous sex hormones and to total levels due to the effect on SHBG levels.
Enhanced anterior pituitary mitotic response to adrenalectomy after multiple glucocorticoid exposures
Authors: Nolan LA , Thomas CK , Levy A
Published: January 2005

OBJECTIVES: Glucocorticoid withdrawal in man is associated with transient but sometimes prolonged impairment of hypothalamo-pituitary-adrenal axis secretory responsiveness. This has led to continued concern in the clinical arena. The acute anterior pituitary response to glucocorticoids in the rat includes apoptosis-mediated deletion of a cell population. Whilst continued cell turnover following glucocorticoid withdrawal and the potential for differentiation of uncommitted precursor cells and transdifferentiation of other secretory cell types predicts that, given sufficient time, complete anterior pituitary trophic recovery is likely, this hypothesis has not previously been tested. DESIGN AND METHODS: We have quantified pituitary mitotic and apoptotic rate, as well as corticotroph number and pro-opiomelanocortin transcript prevalence, together with hypothalamic corticotrophin-releasing hormone and vasopressin transcript prevalence 5 weeks after three short dexamethasone treatments each separated by a week. Bilateral adrenalectomy was then carried out as a maximal secretory and trophic stimulus, and the response to a fourth dexamethasone treatment assessed 1 week later. RESULTS: Anterior pituitary mitotic index was significantly higher in rats previously exposed to dexamethasone compared with age-matched controls exposed to dexamethasone for the first time. No differences were found in the subsequent apoptotic response to a fourth dexamethasone treatment or in the levels of paraventricular corticotrophin-releasing hormone or vasopressin transcripts or pituitary pro-opiomelanocortin transcripts. CONCLUSIONS: These data indicate that full recovery of pituitary mitotic activity takes longer than the recovery of secretory parameters, and suggest that, for several weeks after glucocorticoid exposure, the ability of the pituitary to meet fresh demands placed on it may be suboptimal.
Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action
Authors: Stewart PM
Published: January 2005

Two isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 acts predominantly as an oxo-reductase in vivo using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 is a NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tIssues, both enzymes serve to control the availability of cortisol to bind to corticosteroid receptors. 11beta-HSD2 protects the mineralocorticoid receptor from cortisol excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of 'apparent mineralocorticoid excess', in which 'Cushing's disease of the kidney' results in cortisol-mediated mineralocorticoid excess. Inhibition of 11beta-HSD2 explains the mineralocorticoid excess state seen following liquorice ingestion and more subtle defects in enzyme expression might be involved in the pathogenesis of 'essential' hypertension. 11beta-HSD1 by generating cortisol in an autocrine fashion facilitates glucocorticoid receptor-mediated action in key peripheral tIssues including liver, adipose tissue, bone and the eye. 'Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of central obesity and raises the exciting possibility of selective 11beta-HSD1 inhibition as a novel therapy for patients with the metabolic syndrome. 'Pre-receptor' metabolism of cortisol via 11beta-HSD isozymes is an important facet of corticosteroid hormone action. Aberrant expression of these isozymes is involved in the pathogenesis of diverse human diseases including hypertension, insulin resistance and obesity. Modulation of enzyme activity may offer a future therapeutic approach to treating these diseases whilst circumventing the endocrine consequences of glucocorticoid excess or deficiency.
The future endocrine patient. Reflections on the future of clinical endocrinology
Authors: Lamberts SW , Romijn JA , Wiersinga WM
Published: January 2005

In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we describe 'the endocrine patient' of the past, the present, and the future. Complete therapeutic breakthroughs resulting in 'cure' are compared with 'halfway technologies' which help in creating the (life-long) chronic endocrine patient. The potential use of molecular diagnostics in optimalizing hormone replacement therapy is discussed. Clinical endocrinology is at risk of developing into a subspecialty where life-style drugs created for new diseases or conditions are offered, but also actively pursued by otherwise healthy individuals (e.g. in normal short stature, regulation of appetite, body composition, sexuality, reproduction and aging). The potential opportunities and risks for clinical endocrinology in creating 'the endocrine patient' of the future are discussed.
IGF-I and IGF-binding protein-3 measurements on filter paper blood spots in children and adolescents on GH treatment: use in monitoring and as markers of growth performance
Authors: Das U , Whatmore AJ , Khosravi J , Wales JK , Butler G , Kibirige MS , Diamandi A , Jones J , Patel L , Hall CM , Price DA , Clayton PE
Published: January 2005

BACKGROUND/AIM: In childhood an appropriate response to GH treatment is achieved by titration of growth response against dose administered, with careful observation for side-effects. In order to evaluate the potential use of IGF monitoring in children treated with GH, a cross-sectional study has been carried in 215 children and adolescents (134 with GH deficiency (GHD), 54 with Turner syndrome (TS) and 27 with non-GHD growth disorders) treated with GH for 0.2-13.7 years. METHODS: IGF-I and IGF-binding protein-3 (IGFBP-3) were measured in ELISAs, using dried capillary blood collected onto filter papers. Results were expressed as the mean S.D. range (SDS). Values of either analyte < -2 or > +2 SDS were considered abnormal. RESULTS: IGF-I and IGFBP-3 SDS were higher in the TS and non-GHD groups (mean +0.01 and +0.1 respectively) than in those with GHD (mean value -0.6). Nineteen per cent of the IGF-I values (13% low, 6% high) and 12% of IGFBP-3 values were abnormal (10% low, 2% high). Abnormalities, either low or high, were most common in the GHD group. There was a weak but significant relationship between change in height SDS over the Year up to the time of sampling in the whole group and IGF-I SDS. Satisfactory growth performance (+0.5>change in height SDS> -0.5) was found in those with high (7.2%), normal (60%) and low (9.3%) IGF-I levels. Overall, it was estimated that 26% of the tests would indicate that an adjustment to GH dose (up in 18% and down in 8%) could be considered. CONCLUSIONS: From this cross-sectional study of IGF monitoring across a broad range of diagnoses and ages, it can be concluded that the majority of children on GH have normal levels of IGF-I and IGFBP-3, but 26% of tests could suggest that a change of GH dose should be considered. Regular monitoring of IGF-I and IGFBP-3 should be considered in any child on GH treatment.